[1,8]naphthyridin-2-ones and related compounds for the treatment of schizophrenia

ABSTRACT

This invention relates to compounds of the formula 1  
                 
 
wherein G, D, A, Z, Q, X, Y, R 1 , and R 4  through R 7  are defined as in the specification, processes for preparing the same and intermediates used in making the same, and pharmaceutical compositions containing such compounds and their use in the treatment of central nervous system disorders and other disorders.

BACKGROUND OF THE INVENTION

This invention relates to [1,8]naphthyridin-2-ones and relatedcompounds, methods of making such compounds, pharmaceutical compositionscontaining them, and their use for the treatment of schizophrenia andother central nervous system (CNS).

The [1,8]naphthyridin-2-ones and related compounds of this inventionbind to dopamine D₂ receptors. Some exhibit activity as partial agonistsof D₂ receptors, while others exhibit activity as antagonists of suchreceptors.

Other heterocyclic derivatives that are useful for the treatment ofschizophrenia are referred to in U.S. Pat. No. 5,350,747, which issuedon Sep. 27, 1994, and in U.S. Pat. No. 6,127,357, which issued on Oct.3, 2000. These patents are incorporated herein by reference in theirentireties.

Other heterocyclic derivatives that have been stated to be useful asantipsychotic agents are those referred to in PCT patent publication WO93/04684, which published on Mar. 18, 1993, and European patentapplication EP 402644A, which was published on Dec. 19, 1990. Thesepatent applications are incorporated herein by reference in theirentireties.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula 1

A is —(CH₂)_(m)CH₂—, —(CH₂)_(m)O—, or —(CH₂)_(m)NH—, wherein m is aninteger from 2 to 5 and wherein one or two of the carbon or nitrogenatoms of —(CH₂)_(m)CH₂—, —(CH₂)_(m)O— and —(CH₂)_(m)NH— can besubstituted, optionally and independently, with one or two substituentsthat are selected, independently, from fluoro and methyl, or with twosubstituents attached to the same carbon atom that form, together withthe carbon to which they are attached, a spirocyclopropyl orspirocyclobutyl ring;

D is N, C, or CH, provided that when D is N each carbon atom covalentlyattached to D is attached through a single bond;

Z and Q are independently N, C, or CH, provided that at least one of Zand Q is N;

—X

Y— is —CH₂—CH₂—, —CH═CH—, —CH₂—NH—, —NH—CH₂—, —N═CH—, —CH═N—, —O—CH₂—,or —CH₂—O—, wherein —

Y— can optionally be substituted, at any available bonding site, by oneto four substituents R², R^(2′), R³ and R^(3′);

V and W are independently N, C, or CH;

ring AA is a saturated or unsaturated 5- 6- or 7-membered carbocyclicring wherein one, two or three of the carbon atoms of ring AA that arenot shared with the benzo ring of group (ii) can be replaced, optionallyand independently, by a nitrogen, oxygen or sulfur atom;

R¹ is hydrogen, —C(═O)CH₃, or (C₁-C₃) alkyl;

R², R^(2′), R³ and R^(3′) are independently. selected from hydrogen,halo, cyano, oxo, hydroxy, —C(═O)CH₃, (C₁-C₄) alkyl, and (C₁-C₄) alkoxy,wherein the alkyl moieties of the (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and—C(═O)CH₃ groups can be optionally substituted with from one to threefluoro atoms and can also be optionally substituted with an amino orhydroxy substituent;

R⁴ and R⁵ are independently selected from hydrogen, halo, cyano,hydroxy, —C(═O)CH₃, (C₁-C₄) alkyl, and (C₁-C₄) alkoxy, wherein the alkylmoieties of the (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and —C(═O)CH₃ groups canbe optionally substituted with from one to three fluoro atoms and canalso be optionally substituted with an amino or hydroxy substituent;

R⁶ and R⁷ are selected, independently, from hydrogen and methyl;

R⁸, R⁹, R¹⁰, R¹¹, and R¹² are independently selected from hydrogen,halo, —C(═O)CH₃, (C₁-C₄) alkyl, and (C₁-C₄) alkoxy, aryl, and aryloxy,wherein the alkyl moieties of the (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and—C(═O)CH₃ groups and the aryl and aryloxy moieties can be optionallysubstituted with from one to three fluoro atoms and can also beoptionally substituted with an amino or hydroxy substituent;

R¹³ and R¹⁴ are independently selected from hydrogen, halo, cyano, oxo,hydroxy, —C(═O)CH₃, (C₁-C₄) alkyl, and (C₁-C₄) alkoxy, wherein the alkylmoieties of the (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and —C(═O)CH₃ groups canbe optionally substituted with from one to three fluoro atoms and canalso be optionally substituted with an amino or hydroxy substituent;

and the pharmaceutically acceptable salts of such compounds.

This invention also relates to a pharmaceutical composition comprising atherapeutically effective amount of a compound of the formula 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The compounds of formula 1 have useful pharmaceutical and medicinalproperties.

This invention also relates to a method of treating a disorder orcondition selected from the group consisting of single episodic orrecurrent major depressive disorders, dysthymic disorders, depressiveneurosis and neurotic depression, melancholic depression includinganorexia, weight loss, insomnia, early morning waking or psychomotorretardation; atypical depression (or reactive depression) includingincreased appetite, hypersomnia, psychomotor agitation or irritability,seasonal affective disorder and pediatric depression; bipolar disordersor manic depression, for example, bipolar I disorder, bipolar IIdisorder and cyclothymic disorder; conduct disorder; disruptive behaviordisorder; attention deficit hyperactivity disorder (ADHD); behavioraldisturbances associated with mental retardation, autistic disorder, andconduct disorder; anxiety disorders such as panic disorder with orwithout agoraphobia, agoraphobia without history of panic disorder,specific phobias, for example, specific animal phobias, social anxiety,social phobia, obsessive-compulsive disorder, stress disorders includingpost-traumatic stress disorder and acute stress disorder, andgeneralized anxiety disorders; borderline personality disorder;schizophrenia and other psychotic disorders, for example,schizophreniform disorders, schizoaffective disorders, delusionaldisorders, brief psychotic disorders, shared psychotic disorders,psychotic disorders with delusions or hallucinations, psychotic episodesof anxiety, anxiety associated with psychosis, psychotic mood disorderssuch as severe major depressive disorder; mood disorders associated withpsychotic disorders such as acute mania and depression associated withbipolar disorder; mood disorders associated with schizophrenia;delirium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Parkinson's disease (PD),Huntington's disease (HD), Alzheimer's disease, senile dementia,dementia of the Alzheimer's type, memory disorders, loss of executivefunction, vascular dementia, and other dementias, for example, due toHIV disease, head trauma, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeldt-Jakob disease, or due to multipleetiologies; movement disorders such as akinesias, dyskinesias, includingfamilial paroxysmal dyskinesias, spasticities, Tourette's syndrome,Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidalmovement disorders such as medication-induced movement disorders, forexample, neuroleptic-induced Parkinsonism, neuroleptic malignantsyndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acuteakathisia, neuroleptic-induced tardive dyskinesia and medication-inducedpostural tremor; chemical dependencies and addictions (e.g.,dependencies on, or addictions to, alcohol, heroin, cocaine,benzodiazepines, nicotine, or phenobarbitol) and behavioral addictionssuch as an addiction to gambling; and ocular disorders such as glaucomaand ischemic retinopathy in a mammal, including a human, comprisingadministering to a mammal in need of such treatment an amount of acompound of the formula 1, or a pharmaceutically acceptable saltthereof, that is effective in treating such disorder or condition.

This invention also relates to a pharmaceutical composition for treatingany disorder or condition listed immediately above, the pharmaceuticalcomposition comprising an amount of a compound of the formula 1, or apharmaceutically acceptable salt thereof, that is effective in treatingsuch disorder or condition, and a pharmaceutically acceptable carrier.

This invention also relates to a process for preparing a compound offormula 2, below. The compound of formula 2 is suitable for use as anintermediate in synthesis of compounds of formula 1:

wherein

-   -   P is H, benzyl, p-methyoxybenzyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or tetrahydropyranyl;

n is an integer from 1 to 4;

Q, Z, —X

Y—, R¹, R⁴, and R⁵ are the same as defined for formula 1, above.The process of making a compound of formula 2, comprising reacting acompound of formula 3, below:

wherein

-   -   Q, Z, X, Y, R¹, R⁴, and R⁵ are defined as in formula 1 above;        and

R¹³ is Cl, F, Br, S(O)Me, or SO₂Me,

with a compound of formula: PO(CH₂)_(n)CH₂OH in the presence of a baseand a phase transfer catalyst.

This invention also relates to a process for preparing the compound offormula 1, wherein A is —(CH₂)_(m)O— and m is an integer from 2 to 5,the process comprising reacting a compound of formula 4a:

wherein Q, Z, —X

Y—, R¹, R⁴, and R⁵ are defined as in formula 1, and n is an integer from1 to 4,with a compound of the following formula in the presence of a base:

wherein G is defined as in formula 1, above. In this process, G ispreferably a structure of the following formula:

wherein

AA is a 6-membered saturated or unsaturated carbon ring; and R¹³ and R¹⁴are independently selected from hydrogen, halo, cyano, oxo, hydroxy,—C(═O)CH₃, (C₁-C₄) alkyl, and (C₁-C₄) alkoxy.

[Add Description of Reductive Amination (New Independent Claim)]

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof. Examples of “alkyl” groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,butyl, iso- sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,norbornyl, and the like.

The term “alkoxy”, as used herein, unless otherwise indicated, means“alkyl-O—”, wherein “alkyl” is as defined above. Examples of “alkoxy”groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxyand pentoxy.

The term “aryl”, as used herein, unless otherwise indicated, refers toan aromatic 5- or 6-membered carbocyclic ring wherein one carbon of thering is covalently attached to another subunit of a compound.

The term “aryloxy” as used herein, refers to an aryl wherein one carbonof the aromatic ring is covalently attached to another subunit of acompound through an —O—, oxy, or (C₁-C₄) alkoxy residue.

The term “one or more substituents”, as used herein, refers to a numberof substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites.

The terms “halo” and “halogen”, as used herein, unless otherwiseindicated, include, fluoro, chloro, bromo and iodo.

The term “treating”, as used herein, refers to reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition towhich such term applies, or preventing one or more symptoms of suchcondition or disorder.

The term “treatment”, as used herein, refers to the act of treating, as“treating” is defined immediately above.

The compounds of formula 1, and the pharmaceutically acceptable salts ofthese compounds are referred to herein, collectively, as the “novelcompounds of this invention” and the “active compounds of thisinvention”.

DETAILED DESCRIPTION OF THE INVENTION

Preferred embodiments of this invention relate to compounds of theformula 1, and their pharmaceutically acceptable salts, wherein G is agroup of the formula ii and ring AA is a benzo ring.

Other preferred embodiments of this invention relate to compounds of theformula 1, and their pharmaceutically acceptable salts, wherein —X

Y— is —CH₂—NH—.

Other preferred embodiments of this invention relate to compounds offormula 1 and their pharmaceutically acceptable salts, wherein G isnaphthyl, and R¹³ and R¹⁴ are independently hydrogen or flouro.

Other preferred embodiments of this invention relate to compounds offormula 1 and their pharmaceutically acceptable salts, wherein at leastone of R¹³ or R¹⁴ is flouro or methoxy.

Other preferred embodiments of this invention relate to compounds of theformula 1, and their pharmaceutically acceptable salts, wherein G is agroup of a formula selected from:

Other preferred embodiments of this invention relate to compounds of theformula 1, and their pharmaceutically acceptable salts, wherein G is2,3-dichlorophenyl.

Other preferred embodiments of this invention relate to compounds of theformula 1, and their pharmaceutically acceptable salts, wherein W and Vare C or CH.

Other preferred embodiments of this invention relate to compounds offormula 1 and their pharmaceutically acceptable salts, wherein D is N, Qis N, Z is CH, —X

Y— is —CH₂—CH₂— or —CH═CH—, and R¹, R⁴, and R⁵ are hydrogen.

Other preferred embodiments of this invention relate to compounds offormula 1 and their pharmaceutically acceptable salts, wherein W and Vare C or CH, or wherein only one of W or V is N.

Other preferred embodiments of this invention relate to compounds offormula 1 and their pharmaceutically acceptable salts, wherein Q and Zare both N.

Other preferred embodiments of this invention relate to compounds of theformula 1, and their pharmaceutically acceptable salts, wherein R⁴ andR⁵ are hydrogen.

Other preferred embodiments of this invention relate to compounds of theformula 1, and their pharmaceutically acceptable salts, wherein D is N.

Other preferred embodiments of this invention relate to compounds of theformula 1, and their pharmaceutically acceptable salts, wherein A is—(CH₂)₄O—.

Other preferred embodiments of this invention relate to compounds of theformula 1, and their pharmaceutically acceptable salts, wherein Q is Nand Z is C or CH.

Other preferred embodiments of this invention relate to compounds of theformula 1, and their pharmaceutically acceptable salts, wherein Q is Nand Z is N.

Other preferred embodiments of this invention relate to compounds of theformula 1, and their pharmaceutically acceptable salts, wherein —X

Y— is —CH₂—CH₂— or —CH═CH—.

Other preferred embodiments of this invention relate to compounds of theformula 1, and their pharmaceutically acceptable salts, wherein R¹ ishydrogen.

Other embodiments of this invention relate to compounds of the formula1, and their pharmaceutically acceptable salts, wherein Q is C or CH,and Z is N.

Other embodiments of this invention relates to compounds of the formula1, and their pharmaceutically acceptable salts, wherein —X

Y— is —O—CH₂—.

Other embodiments of this invention relates to compounds of the formula1, and their pharmaceutically acceptable salts, wherein —X

Y— is —CH₂—O—.

Other embodiments of this invention relate to compounds of the formula1, and their pharmaceutically acceptable salts, wherein A is—(CH₂)_(m)—CH₂— wherein m is 3 or 4.

Other embodiments of this invention relate to compounds of the formula 1and their pharmaceutically acceptable salts, wherein G is a group of theformula (i) and W and V are both N, or W is N and V is C or CH.

One set of specific embodiments of the invention relate to compounds offormula 1 and their pharmaceutically acceptable salts, wherein all ofthe atoms of the carbocyclic ring AA are carbon atoms. These embodimentsinclude the following compounds and their pharmaceutically acceptablesalts. Procedures for synthesis of each of these compounds areillustrated in the Examples section, below.

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Chloro-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Chloro-2-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Biphenyl-2-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,5-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-4-fluoro-5-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5-Chloro-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Ethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Chloro-2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Methyl-2-phenoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dimethoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Ethoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-3-ethoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-3-isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Methoxy-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5-Chloro-2-isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Isobutoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Acetyl-3-chloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Chloro-2-ethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Acetyl-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Ethyl-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Acetyl-2-chloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Acetyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Acetyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Ethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-o-Tolyl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Phenyl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,4-Difluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[2-(1,1-Difluoro-ethyl)-phenyl]-piperazin-1-yl}-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Pyridin-2-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(4-Methyl-pyrimidin-2-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Fluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(8-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7,7-Dimethyl-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7,7-Difluoro-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7,7-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5,5-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Difluoro-indan-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6,7,8,9-Tetrahydro-5H-benzocyclohepten-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Naphthalen-1-yl-piperidin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(4-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(8-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(4-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

8-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyl]-piperazin-1-yl}-naphthalene-2-carbonitrile;

N-(8-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyl]-piperazin-1-yl}-naphthalen-2-yl)-acetamide;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Acetyl-3-chloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Chloro-2-ethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Acetyl-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Acetyl-2-chloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-4-fluoro-5-methyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5-Chloro-2-isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Isobutoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-[4-(4-o-Tolyl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

7-{4-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[2-(1,1-Difluoro-ethyl)-phenyl]-piperazin-1-yl}-butoxy)-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-3-ethoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-3-isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Methyl-2-phenoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Chloro-2-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Biphenyl-2-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Methoxy-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Pyrimidin-2-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(4-Methoxy-pyrimidin-2-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Fluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(8-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7,7-Dimethyl-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7,7-Dimethyl-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7,7-Difluoro-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7,7-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5,5-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Difluoro-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(4-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(8-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(4-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

8-{4-[4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyl]-piperazin-1-yl}-naphthalene-2-carbonitrile;

1-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-{3-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-propoxy}-1H-[1,8]naphthyridin-2-one;

7-[3-(4-Naphthalen-1-yl-piperazin-1-yl)-propoxy]-1H-[1,8]naphthyridin-2-one;

7-[3-(4-Naphthalen-1-yl-piperazin-1-yl)-propoxyl]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{2-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-ethoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-1-methyl-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[1-Methyl-4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-1,1-dimethyl-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[1,1-Dimethyl-4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{5-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{5-[4-(2,3-Dichloro4-fluoro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[5-(4-Naphthalen-1-yl-piperazin-1-yl)-pentyl]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{5-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{5-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{5-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{5-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{5-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{5-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4-methyl-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-4-methyl-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-methyl-1H-[1,8]naphthyridin-2-one;

7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3-methyl-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dimethyl-1H-[1,8]naphthyridin-2-one;

7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dimethyl-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-fluoro-1H-[1,8]naphthyridin-2-one;

3-Fluoro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3-(2,2,2-trifluoro-ethyl)-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4-hydroxy-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

4,4-Dimethyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

4,4-Dimethyl-7-{4-[4-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Chloro-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Ethyl-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Isobutoxy-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-6-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-6-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

6-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-6-fluoro-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

6-Fluoro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

6-Fluoro-7-[4-(4-indan-4-yl-piperazin-1-yl)-butoxyl]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

6-Chloro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

6-Bromo-7-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

6-Bromo-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-5-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

5-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

5-Methyl-7-{4-[4-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-5-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-5-trifluoromethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-5-trifluoromethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5-trifluoromethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;

7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;

7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;

7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;

7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;

8-{4-[4-(2-Oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-7-yloxy)-butyl]-piperazin-1-yl}-naphthalene-2-carbonitrile;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-methyl-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;

3-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;

7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-4,4-dimethyl-1,4-dihydro-pyrido[2,3-d][1,3]oxazin-2-one;

6-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one;

6-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pentyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one;

6-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one;

6-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-4H-pyrido[3,2-b][1,4]oxazin-3-one;

6-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-4H-pyrido[3,2-b][1,4]oxazin-3-one;

6-{4-[4-(6-Methoxy-pyridin-2-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one;

6-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one;

6-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one;

2-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one;

2-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one;

2-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one;

6-Fluoro-4-methyl-2-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(6-Isopropyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;

2-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;

4-Methyl-2-{4-[4-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;

4-Methyl-2-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4,8-dimethyl-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4,8-dimethyl-8H-pyrido[2,3-d]pyrimidin-7-one;

7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

8-Bromo-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

8-Bromo-7-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

8-Chloro-7-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

8-Chloro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-2-oxo-1,2,3,4-tetrahydro-[1,6]naphthyridine-8-carboxylicacid methyl ester;

8-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,6]naphthyridin-2-one;

7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-1H-[1,6]naphthyridin-2-one;

7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butylamino}-1H-[1,6]naphthyridin-2-one;and7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-4,4-dimethyl-1,4-dihydro-pyrido[4,3-d][1,3]oxazin-2-one.

This same set of specific embodiments further includes the followingcompounds and their pharmaceutically acceptable salts:

7-{4-[4-(7-Trifluoromethyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Trifluoromethyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[7-(2-Hydroxy-ethoxy)-naphthalen-1-yl]-piperazin-1-yl}-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[7-(2-Methoxy-ethoxy)-naphthalen-1-yl]-piperazin-1-yl}-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[7-(2-Amino-ethoxy)-naphthalen-1-yl]-piperazin-1-yl}-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[7-(2-Dimethylamino-ethoxy)-naphthalen-1-yl]-piperazin-1-yl}-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[7-(2-Hydroxy-ethoxy)-naphthalen-1-yl]-piperazin-1-yl}-butoxy)-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[7-(2-Methoxy-ethoxy)-naphthalen-1-yl]-piperazin-1-yl}-butoxy)-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[7-(2-Amino-ethoxy)-naphthalen-1-yl]-piperazin-1-yl}-butoxy)-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[7-(2-Dimethylamino-ethoxy)-naphthalen-1-yl]-piperazin-1-yl}-butoxy)-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperidin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Chloro-3-ethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7,8-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7,8-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6,8-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6,8-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(8-Trifluoromethyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(8-Trifluoromethyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Dimethyl-indan-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Dimethyl-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Difluoro-3-oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Difluoro-3-oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Dimethyl-3-oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Dimethyl-3-oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5-methyl-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5-methyl-1H-[1,8]naphthyridin-2-one;

6-Fluoro-7-{4-[4-(7-fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

6-Fluoro-7-{4-[4-(7-fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

6-Fluoro-7-{4-[4-(8-fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

6-Fluoro-7-{4-[4-(8-fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-6-fluoro-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;

6-Fluoro-2-{4-[4-(7-fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;

6-Fluoro-2-{4-[4-(8-fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;

4,4-Dimethyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-1,4-dihydro-pyrido[2,3-d][1,3]oxazin-2-one;

6-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-4H-pyrido[2,3-b]pyrazin-3-one;

6-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1,4-dihydro-2H-pyrido[2,3-b]pyrazin-3-one;

7-{3-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-propoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{3-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-propoxy}-1H-[1,8]naphthyridin-2-one;and

7-[5-(4-Naphthalen-1-yl-piperazin-1-yl)-pentyloxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one.

Another set of specific embodiments of the invention relate to compoundsof formula 1 and their pharmaceutically acceptable salts, wherein atleast one of the carbon atoms of the carbocyclic ring AA that are notshared with the benzo ring of group (ii) has been replaced,independently, by a nitrogen, oxygen, or sulfur atom. These embodimentsinclude the following compounds and their pharmaceutically acceptablesalts. Procedures for synthesis of each of these compounds areillustrated in the Examples, below.

7-{4-[4-(2-Oxo-2,3-dihydro-benzooxazol-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Dimethyl-2H-chromen-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(Spiro[chromene-2,1′-cyclopentan]-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3,4-Dihydrospiro[chromene-2,1′-cyclopentan]-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Methyl-2H-chromen-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Methyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dihydro-benzofuran-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1,3-Dihydro-isobenzofuran-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Chroman-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Isochroman-5-yl-piperazin-1-yl)-butoxyl]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Isochroman-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(4-Oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3,3-Dimethyl-4-oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3,3-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Benzofuran-7-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1H-Indol-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1H-Indol4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1-Methyl-1H-indol-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Benzo[1,2,5]oxadiazol-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Trifluoromethyl-3H-benzoimidazol-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1-Methyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1-Ethyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Quinolin-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Quinolin-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Isoquinolin-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Isoquinolin-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Fluoro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Fluoro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Methyl-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Ethoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Methoxy-quinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Quinoxalin-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Dimethylamino-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Methylamino-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Oxo-1,2-dihydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Dimethyl-2H-chromen-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Methyl-2H-chromen-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Methyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(Spiro[chromene-2,1′-cyclopentan]-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3,4-Dihydrospiro[chromene-2,1′-cyclopentan]-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Chroman-5-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dihydro-benzofuran-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1,3-Dihydro-isobenzofuran-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(4-Oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3,3-Dimethyl-4-oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3,3-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Isochroman-5-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Isochroman-8-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Quinolin-8-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Quinolin-5-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Quinoxalin-5-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1-H-[1,8]naphthyridin-2-one;

7-[4-(4-Benzofuran-7-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1-Acetyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1-Methyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1-Ethyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Ethoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Dimethylamino-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Methylamino-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Fluoro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Fluoro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Oxo-1,2-dihydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1-H-[1,8]naphthyridin-2-one;7-{4-[4-(2-Oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Benzo[1,2,5]oxadiazol-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Trifluoromethyl-3H-benzoimidazol-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

4,4-Dimethyl-7-[4-(4-quinolin-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

4,4-Dimethyl-7-{4-[4-(2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

4,4-Dimethyl-7-{4-[4-(2-oxo-1,2-dihydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Benzofuran-7-yl-piperazin-1-yl)-butoxy]-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

6-Fluoro-7-[4-(4-quinolin-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

6-Fluoro-7-[4-(4-isoquinolin-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-1H-pyrido[2,3-d]pyrimidin-2-one;

7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;

7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;

7-{4-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;

6-{4-[4-(2-Methyl-quinolin-8-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one;

6-[4-(4-Quinolin-8-yl-piperazin-1-yl)-butoxy]-4H-pyrido[3,2-b][1,4]oxazin-3-one;

6-{4-[4-(2-Oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one;

6-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-4H-pyrido[3,2-b][1,4]oxazin-3-one;

6-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one;

2-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one;

2-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one;

2-[4-(4-Quinolin-8-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(2,2-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(2-Methyl-quinolin-8-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;

2-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;

2-[4-(4-Benzofuran-7-yl-piperazin-1-yl)-butoxy]-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;

2-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;

4-Methyl-2-{4-[4-(2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one;

4-Methyl-2-[4-(4-quinolin-8-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one;

7-[4-(4—-Chroman-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-1H-[1,6]naphthyridin-2-one;

7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,6]naphthyridin-2-one;

7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-1H-[1,6]naphthyridin-2-one;and

7-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,6]naphthyridin-2-one.

This same set of specific embodiments further includes the followingcompounds and their pharmaceutically acceptable salts:

7-(4-{4-[2-(2-Hydroxy-ethoxy)-quinolin-8-yl]-piperazin-1-yl}-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[2-(2-Methoxy-ethoxy)-quinolin-8-yl]-piperazin-1-yl}-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[2-(2-Amino-ethoxy)-quinolin-8-yl]-piperazin-1-yl}-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[2-(2-Dimethylamino-ethoxy)-quinolin-8-yl]-piperazin-1-yl}-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[2-(2-Hydroxy-ethoxy)-quinolin-8-yl]-piperazin-1-yl}-butoxy)-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[2-(2-Methoxy-ethoxy)-quinolin-8-yl]-piperazin-1-yl}-butoxy)-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[2-(2-Amino-ethoxy)-quinolin-8-yl]-piperazin-1-yl}-butoxy)-1H-[1,8]naphthyridin-2-one;

7-(4-{4-[2-(2-Dimethylamino-ethoxy)-quinolin-8-yl]-piperazin-1-yl}-butoxy)-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Hydroxymethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Aminomethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Hydroxy-2,2-dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Dimethyl-3-oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Hydroxymethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Aminomethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Hydroxy-2,2-dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,2-Dimethyl-3-oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Methyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Hydroxymethyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Aminomethyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

5-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyl]-piperazin-1-yl}-chroman-3-carbonitrile;

7-{4-[4-(3,3-Dimethyl-4-oxo-chroman-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3,3-Dimethyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(4-Methyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Methyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Hydroxymethyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Aminomethyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

5-{4-[4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyl]-piperazin-1-yl}-chroman-3-carbonitrile;

7-{4-[4-(3,3-Dimethyl-4-oxo-chroman-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3,3-Dimethyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(4-Methyl-chroman-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-[3-(4-Chroman-8-yl-piperazin-1-yl)-propoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[3-(4-Chroman-8-yl-piperazin-1-yl)-propoxy]-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1,2,3,4-Tetrahydro-isoquinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1,2,3,4-Tetrahydro-isoquinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1,2,3,4-Tetrahydro-isoquinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(1,2,3,4-Tetrahydro-isoquinolin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Ethyl-2,3-dihydro-1H-isoindol-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

8-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyl]-piperazin-1-yl}-quinoline-2-carbonitrile;

8-{4-[4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyl]-piperazin-1-yl}-quinoline-2-carbonitrile;

7-{4-[4-(3-Methoxy-isoquinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(3-Methoxy-isoquinolin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

5-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyl]-piperazin-1-yl}-quinoline-3-carbonitrile;

5-{4-[4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyl]-piperazin-1-yl}-quinoline-3-carbonitrile;

7-{4-[4-(3-Chloro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;and

7-{4-[4-(3-Chloro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

The following compounds and their pharmaceutically acceptable salts arepreferred embodiments of the compound of formula 1:

7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

4-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

4,4-Dimethyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

5-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-5-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

6-Fluoro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;

3-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;

7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;

7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;

2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one;and

6-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one

The following compounds and their pharmaceutically acceptable salts areparticularly preferred embodiments of the compound of formula 1:

7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;

7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;and

2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one.

Compounds of the formula 1 may contain chiral centers and therefore mayexist in different enantiomeric and diastereomeric forms. This inventionrelates to all optical isomers and all stereoisomers of compounds of theformula 1, both as racemic mixtures and as individual enantiomers anddiastereoisomers of such compounds, and mixtures thereof, and to allpharmaceutical compositions and methods of treatment defined above thatcontain or employ them, respectively. Individual isomers can be obtainedby known methods, such as optical resolution, fractionalcrystallization, optically selective reaction, or chromatographicseparation in the preparation of the final product or its intermediate.Individual enantiomers of the compounds of formula 1 may haveadvantages, as compared with the racemic mixtures of these compounds, inthe treatment of various disorders or conditions.

In so far as the compounds of formula 1 are basic compounds, they areall capable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate the base compound from thereaction mixture as a pharmaceutically unacceptable salt and then simplyconvert to the free base compound by treatment with an alkaline reagentand thereafter convert the free base to a pharmaceutically acceptableacid addition salt. The acid addition salts of the base compounds ofthis invention are readily prepared by treating the base compound with asubstantially equivalent amount of the chosen mineral or organic acid inan aqueous solvent or in a suitable organic solvent, such as methanol orethanol. Upon careful evaporation of the solvent, the desired solid saltis readily obtained. The acids which are used to prepare thepharmaceutically acceptable acid addition salts of the aforementionedbase compounds of this invention are those which form non-toxic acidaddition salts, i.e., salts containing pharmaceutically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate,citrate or acid citrate, tartrate or bi-tartrate, succinate, maleate,fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

The present invention also includes isotopically labeled compounds,which are identical to those of formula 1, but for the fact that one ormore atoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds of thepresent invention include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C,¹¹C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certain isotopicallylabeled compounds of the present invention, for example those into whichradioactive isotopes such as ³H and ¹⁴C are incorporated, are useful indrug and/or substrate tissue distribution assays. Tritiated, i.e., ³H,and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution withheavier isotopes such as deuterium, i.e., ²H, can afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements and,hence, may be preferred in some circumstances. Isotopically labeledcompounds of formula 1 and prodrugs thereof can generally be prepared bycarrying out the procedures disclosed in the Schemes and/or in theExamples below, by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

In one specific embodiment of the method of the present invention oftreating a disorder or condition, the disorder or condition that isbeing treated is selected from major depression, single episodedepression, recurrent depression, child abuse induced depression,postpartum depression, dysthymia, cyclothymia and bipolar disorder.

Another more specific embodiment of this invention relates to the abovemethod wherein the disorder or condition that is being treated isselected from schizophrenia, schizoaffective disorder, delusionaldisorder, substance-induced psychotic disorder, brief psychoticdisorder, shared psychotic disorder, psychotic disorder due to a generalmedical condition, and schizophreniform disorder.

Another more specific embodiment of this invention relates to the abovemethod wherein the disorder or condition that is being treated isselected from autism, pervasive development disorder, speech impedimentssuch as stuttering, and attention deficit hyperactivity disorder.

Another more specific embodiment of this invention relates to the abovemethod wherein the disorder or condition that is being treated isselected from generalized anxiety disorder, panic disorder,obsessive-compulsive disorder, post-traumatic stress disorder, andphobias, including social phobia, agoraphobia, and specific phobias.

Another more specific embodiment of this invention relates to the abovemethod wherein the disorder or condition that is being treated isselected from movement disorders such as akinesias, dyskinesias,including familial paroxysmal dyskinesias, spasticities, Tourette'ssyndrome, Scott syndrome, PALSYS and akinetic-rigid syndrome; andextra-pyramidal movement disorders such as medication-induced movementdisorders, for example, neuroleptic-induced Parkinsonism, neurolepticmalignant syndrome, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia and medication-induced postural tremor.

Another more specific embodiment of this invention relates to the abovemethod wherein the disorder or condition that is being treated isselected from delirium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Parkinson's disease (PD),Huntington's disease (HD), Alzheimer's disease, senile dementia,dementia of the Alzheimer's type, memory disorder, vascular dementia,and other dementias, for example, due to HIV disease, head trauma,Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeldt-Jakob disease, or due to multiple etiologies.

Another more specific embodiment of this invention relates to the abovemethod wherein the compound of formula 1 is administered to a human forthe treatment of any two or more comorbid disorders or conditionsselected from those disorders and conditions referred to in any of theabove methods.

For the treatment of depression, anxiety, schizophrenia or any of theother disorders and conditions referred to above in the descriptions ofthe methods and pharmaceutical compositions of this invention, the novelcompounds of this invention can be used in conjunction with one or moreother antidepressants or anti-anxiety agents. Examples of classes ofantidepressants that can be used in combination with the activecompounds of this invention include norepinephrine reuptake inhibitors,selective serotonin reuptake inhibitors (SSRIs), NK-1 receptorantagonists, monoamine oxidase inhibitors (MAOIs), reversible inhibitorsof monoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, and atypical antidepressants. Suitablenorepinephrine reuptake inhibitors include tertiary amine tricyclics andsecondary amine tricyclics. Suitable tertiary amine tricyclics andsecondary amine tricyclics include amitriptyline, clomipramine, doxepin,imipramine, trimipramine, dothiepin, butripyline, iprindole,lofepramine, nortriptyline, protriptyline, amoxapine, desipramine andmaprotiline. Suitable selective serotonin reuptake inhibitors includefluoxetine, fluvoxamine, paroxetine and sertraline. Examples ofmonoamine oxidase inhibitors include isocarboxazid, phenelzine, andtranylcyclopramine. Suitable reversible inhibitors of monoamine oxidaseinclude moclobemide. Suitable serotonin and noradrenaline reuptakeinhibitors of use in the present invention include venlafaxine. SuitableCRF antagonists include those compounds described in InternationalPatent Application Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO94/13676 and WO 94/13677. Suitable atypical anti-depressants includebupropion, lithium, nefazodone, trazodone and viloxazine. Suitable NK-1receptor antagonists include those referred to in World PatentPublication WO 01/77100.

Suitable classes of anti-anxiety agents that can be used in combinationwith the active compounds of this invention include benzodiazepines andserotonin 1A (5-HT_(1A)) agonists or antagonists, especially 5-HT_(1A)partial agonists, and corticotropin releasing factor (CRF) antagonists.Suitable benzodiazepines include alprazolam, chlordiazepoxide,clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam, andprazepam. Suitable 5-HT_(1A) receptor agonists or antagonists includebuspirone, flesinoxan, gepirone and ipsapirone.

This invention also relates to a method of treating a disorder orcondition selected from single episodic or recurrent major depressivedisorders, dysthymic disorders, depressive neurosis and neuroticdepression, melancholic depression including anorexia, weight loss,insomnia, early morning waking or psychomotor retardation; atypicaldepression (or reactive depression) including increased appetite,hypersomnia, psychomotor agitation or irritability, seasonal affectivedisorder and pediatric depression; bipolar disorders or manicdepression, for example, bipolar I disorder, bipolar II disorder andcyclothymic disorder; conduct disorder; disruptive behavior disorder;attention deficit hyperactivity disorder (ADHD); behavioral disturbancesassociated with mental retardation, autistic disorder, and conductdisorder; anxiety disorders such as panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobias, for example, specific animal phobias, social anxiety, socialphobia, obsessive-compulsive disorder, stress disorders includingpost-traumatic stress disorder and acute stress disorder, andgeneralized anxiety disorders; borderline personality disorder;schizophrenia and other psychotic disorders, for example,schizophreniform disorders, schizoaffective disorders, delusionaldisorders, brief psychotic disorders, shared psychotic disorders,psychotic disorders with delusions or hallucinations, psychotic episodesof anxiety, anxiety associated with psychosis, psychotic mood disorderssuch as severe major depressive disorder; mood disorders associated withpsychotic disorders such as acute mania and depression associated withbipolar disorder; mood disorders associated with schizophrenia;delirium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Parkinson's disease (PD),Huntington's disease (HD), Alzheimer's disease, senile dementia,dementia of the Alzheimer's type, memory disorders, loss of executivefunction, vascular dementia, and other dementias, for example, due toHIV disease, head trauma, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeldt-Jakob disease, or due to multipleetiologies; movement disorders such as akinesias, dyskinesias, includingfamilial paroxysmal dyskinesias, spasticities, Tourette's syndrome,Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidalmovement disorders such as medication-induced movement disorders, forexample, neuroleptic-induced Parkinsonism, neuroleptic malignantsyndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acuteakathisia, neuroleptic-induced tardive dyskinesia and medication-inducedpostural tremor; chemical dependencies and addictions (e.g.,dependencies on, or addictions to, alcohol, heroin, cocaine,benzodiazepines, nicotine, or phenobarbitol) and behavioral addictionssuch as an addiction to gambling; and ocular disorders such as glaucomaand ischemic retinopathy in a mammal in need of such treatment,including a human, comprising administering to said mammal:

(a) a compound of the formula 1, or a pharmaceutically acceptable saltthereof; and

(b) another pharmaceutically active compound that is an antidepressantor anti-anxiety agent, or a pharmaceutically acceptable salt thereof;

wherein the active compounds “a” and “b” are present in amounts thatrender the combination effective in treating such disorder or condition.

A more specific embodiment of this invention relates to the above methodwherein the disorder or condition that is being treated is selected frommajor depression, single episode depression, recurrent depression, childabuse induced depression, postpartum depression, dysthymia, cyclothymiaand bipolar disorder.

Another more specific embodiment of this invention relates to the abovemethod wherein the disorder or condition that is being treated isselected from schizophrenia, schizoaffective disorder, delusionaldisorder, substance-induced psychotic disorder, brief psychoticdisorder, shared psychotic disorder, psychotic disorder due to a generalmedical condition, and schizophreniform disorder.

Another more specific embodiment of this invention relates to the abovemethod wherein the disorder or condition that is being treated isselected from autism, pervasive development disorder, and attentiondeficit hyperactivity disorder (ADHD).

Another more specific embodiment of this invention relates to the abovemethod wherein the disorder or condition that is being treated isselected from generalized anxiety disorder, panic disorder,obsessive-compulsive disorder, post-traumatic stress disorder, andphobias, including social phobia, agoraphobia, and specific phobias.

Another more specific embodiment of this invention relates to the abovemethod wherein the disorder or condition that is being treated isselected from movement disorders such as akinesias, dyskinesias,including familial paroxysmal dyskinesias, spasticities, Tourette'ssyndrome, Scott syndrome, PALSYS and akinetic-rigid syndrome; andextra-pyramidal movement disorders such as medication-induced movementdisorders, for example, neuroleptic-induced Parkinsonism, neurolepticmalignant syndrome, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia and medication-induced postural tremor.

Another more specific embodiment of this invention relates to the abovemethod wherein the disorder or condition that is being treated isselected from delirium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Parkinson's disease (PD),Huntington's disease (HD), Alzheimer's disease, senile dementia,dementia of the Alzheimer's type, memory disorders, loss of executivefunction, vascular dementia, and other dementias, for example, due toHIV disease, head trauma, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeldt-Jakob disease, or due to multipleetiologies.

Another more specific embodiment of this invention relates to the abovemethod wherein the compound of formula 1 and the additionalantidepressant or anti-anxiety agent are administered to a human for thetreatment of any two or more comorbid disorders or conditions selectedfrom those disorders and conditions referred to in any of the abovemethods.

This invention also relates to a pharmaceutical composition for treatinga disorder or condition selected from single episodic or recurrent majordepressive disorders, dysthymic disorders, depressive neurosis andneurotic depression, melancholic depression including anorexia, weightloss, insomnia, early morning waking or psychomotor retardation;atypical depression (or reactive depression) including increasedappetite, hypersomnia, psychomotor agitation or irritability, seasonalaffective disorder and pediatric depression; bipolar disorders or manicdepression, for example, bipolar I disorder, bipolar II disorder andcyclothymic disorder; conduct disorder; disruptive behavior disorder;attention deficit hyperactivity disorder (ADHD); behavioral disturbancesassociated with mental retardation, autistic disorder, and conductdisorder; anxiety disorders such as panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobias, for example, specific animal phobias, social anxiety, socialphobia, obsessive-compulsive disorder, stress disorders includingpost-traumatic stress disorder and acute stress disorder, andgeneralized anxiety disorders; borderline personality disorder;schizophrenia and other psychotic disorders, for example,schizophreniform disorders, schizoaffective disorders, delusionaldisorders, brief psychotic disorders, shared psychotic disorders,psychotic disorders with delusions or hallucinations, psychotic episodesof anxiety, anxiety associated with psychosis, psychotic mood disorderssuch as severe major depressive disorder; mood disorders associated withpsychotic disorders such as acute mania and depression associated withbipolar disorder; mood disorders associated with schizophrenia;delirium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Parkinson's disease (PD),Huntington's disease (HD), Alzheimer's disease, senile dementia,dementia of the Alzheimer's type, memory disorders, loss of executivefunction, vascular dementia, and other dementias, for example, due toHIV disease, head trauma, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeldt-Jakob disease, or due to multipleetiologies; movement disorders such as akinesias, dyskinesias, includingfamilial paroxysmal dyskinesias, spasticities, Tourette's syndrome,Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidalmovement disorders such as medication-induced movement disorders, forexample, neuroleptic-induced Parkinsonism, neuroleptic malignantsyndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acuteakathisia, neuroleptic-induced tardive dyskinesia and medication-inducedpostural tremor; chemical dependencies and addictions (e.g.,dependencies on, or addictions to, alcohol, heroin, cocaine,benzodiazepines, nicotine, or phenobarbitol) and behavioral addictionssuch as an addiction to gambling; and ocular disorders such as glaucomaand ischemic retinopathy in a mammal in need of such treatment,including a human, comprising:

(a) a compound of the formula 1, or a pharmaceutically acceptable saltthereof;

(b) another pharmaceutically active compound that is an antidepressantor anti-anxiety agent, or a pharmaceutically acceptable salt thereof;and

(c) a pharmaceutically acceptable carrier;

wherein the active compounds “a” and “b” are present in amounts thatrender the composition effective in treating such disorder or condition.

The active compounds of this invention may be prepared as describedbelow. Unless otherwise indicated, in the reaction schemes anddiscussion that follow, A, Z, D, W, Q, ring AA, G, X, Y, R¹ through R¹⁴,formula 1, the dotted line connecting X and Y, and groups of theformulas (i) and (ii) are defined as above.

Scheme A illustrates a method for preparing compounds of the formula 1wherein A is —(CH₂)_(m)O—, optionally substituted as indicated in thedefinition of formula 1 above (also referred to as compounds of theformula 1A). This method involves oxidation of a compound of the formula2 with Dess-Martin Periodinane or another suitable oxidizing agent suchas IBX (o-iodoxybenzoic acid), oxalyl chloride in dimethyl sulfoxide(DMSO) (Swern oxidation) or PCC (pyridinium chlorochromate) to form thecorresponding aldehyde of formula 3. This reaction may be carried out indichloromethane (CH₂Cl₂), tetrahydrofuran (THF), dimethyl sulfoxide(DMSO) or a combination of two or more of these solvents. Reductiveamination of a G-substituted piperidine or piperizine, as shown inScheme A, using methods well known to those of skill in the art, with acompound of formula 3 yields the corresponding compound of formula 1A.The reductive amination can be performed, for example, utilizingcatalytic hydrogenation methods or using a hydride reducing agent suchas sodium triacetoxyborohydride or sodium cyanoborohydride. The reactionsolvent can be 1,2-dichloroethane, tetrahydrofuran, acetonitrile,dimethylformamide or a combination of two or more of these solvents,with the optional addition of 1-10 equivalents of acetic acid. When thepiperazine or piperidine hydrochloride or hydrobromide salt is used, abase such as triethylamine is typically added.

Alternatively, compounds of the formula 1A can be prepared according toScheme B. The hydroxy group of the compound of formula 2 is convertedinto a leaving group (L) using conventional methods to provide thecorresponding compound of formula 4 wherein L is mesylate (OMs),tosylate (OTs) or a halogen such as bromide, iodide or chloride. L ispreferably chlorine. The resulting compound of formula 4 is then reactedwith a G-substituted piperazine or piperidine, as depicted in Scheme B,to yield the desired compound of formula 1A. This reaction is preferablyrun in the presence of a base such as potassium carbonate, sodiumcarbonate, cesium carbonate, triethylamine or diisopropylethylamine. Thesolvent used may be acetonitrile, water, tetrahydrofuran, dioxane,acetone, methyl isobutyl ketone, benzene or toluene, or a combination oftwo or more of these solvents. Inorganic salts such as sodium orpotassium iodide may be employed as catalysts in the reaction. Thetemperature of the reaction may vary from about ambient temperature toabout the reflux temperature of the solvent used. The reaction may alsobe conducted under microwave irradiation.

Scheme C illustrates a method for preparing compounds of the formula 2A(wherein X is double bonded to Y) and 2B (wherein X is single bonded toY). Addition of 2 to 20 equivalents of a diol of the formulaHOCH₂(CH₂)_(n)OH, wherein n is an integer from 1 to 4, or 1 to 4equivalents of a suitably mono-protected diol of the formulaPOCH₂(CH₂)_(n)OH, wherein n is an integer between 1 and 4 and P istetrahydropyranyl (THP), benzyl (Bn), p-methoxybenzyl,tert-butyldimethysilyl (TBS), or tert-butyldiphenylsilyl (TBDPS), to acompound of the formula 5, wherein R¹³ is chloro, fluoro, bromo, S(O)CH₃or SO₂CH₃, provides the corresponding compound of formula 6 (or 2A whenthe unprotected diol reactant is used). R¹³ is most preferably fluoro.This reaction is conducted in the presence of a base such as potassiumtert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride,lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassiumbis(trimethylsilyl)amide, or sodium bis(trimethylsilyl)amide. Suitablesolvents for this reaction include tetrahydrofuran (THF), dioxane,ethylene glycol dimethylether, dimethylformamide (DMF),N-methylpyrrolidinone (NMP), or dimethylsulfoxide (DMSO), or acombination of two or more of these solvents. The temperature of thereaction may vary from about ambient temperature to about the refluxtemperature of the solvent used.

The reaction of the compound of formula 5 with the 2 to 20 equivalentsof the diol of the formula HOCH₂(CH₂)_(n)OH, wherein n is an integerfrom 1 to 4, or the 1 to 4 equivalents of the mono-protected diol of theformula POCH₂(CH₂)_(n)OH to yield the compound of formula 6, asdescribed above, is preferably conducted in the presence of a catalyticamount of a phase transfer catalyst, such as tetrabutyl ammoniumchloride or bromide. The use of a phase transfer catalyst acceleratesthe rate of the coupling, and allows one to carry out the reaction at alower temperature than would be possible without the catalyst. Use ofthe phase transfer catalyst also significantly reduces the formation ofdimeric by-products.

Compounds of the formula 6 where, P is tetrahydropyranyl (THP), can bedeprotected using conventional methods such as treatment with PPTS(pyridinium p-tolunesulfonate) or p-toluenesulfonic acid in ethanol togive the corresponding compounds of formula 2A. Compounds of the formula6 wherein P is tert-butyldimethysilyl or tert-butyldiphenylsilyl can bedeprotected using conventional methods such as treatment withtetrabutylammonium fluoride in tetrahydrofuran to yield compounds of theformula 2A.

Compounds of the formula 2A or compounds of the formula 6 wherein P is Hor benzyl can be reduced using catalytic hydrogenation methods toprovide the corresponding compounds of formula 2B. For example, thehydrogenation can be conducted using 5 to 20% palladium on activatedcarbon in a solvent such as methanol, ethanol, tetrahydrofuran, aceticacid, dimethylformamide, or a combination of two or more of thesesolvents for a period of about 5 hours to about 48 hours, preferably forabout 24 hours, under a hydrogen pressure from about 1 to about 5atmosphere, preferably about 1 atmosphere.

Alternatively, compounds of the formula 2B can be prepared byhydrogenating, using methods well known to those of skill in the art,such as those described above, compounds of the formula 8, depictedbelow,

which are identical to compounds of the formula 6, wherein P is benzyl,but wherein the oxo substituent is replaced by a benzyloxy substituent.

Compounds of the formula 2B can be prepared, alternatively, by firstdeprotecting and then hydrogenating the corresponding compounds offormula 8, using methods well known to those of skill in the art, suchas those described above. Compounds of the formula 8 can be prepared bya method analogous to that used to prepare compounds of the formula 6 inScheme C, but wherein the reactant of formula 5 is replaced by acompound having formula 7, as depicted below.

Compounds of the formula 7 can be prepared by reacting the correspondingcompounds of formula 5A wherein R¹³ is chloro with benzyl bromide andsilver carbonate in refluxing toluene. Compounds of the formula 7wherein Z is CR⁵ can be prepared, alternatively, by reacting the2,7-dichloro-[1,8]naphthyridine with one equivalent of benzyl alcohol inthe presence of a base such as such as potassium tert-butoxide, sodiumtert-butoxide, sodium hydride, potassium hydride, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, potassiumbis(trimethylsilyl)amide, or sodium bis(trimethylsilyl)amide. Suitablesolvents for this reaction include tetrahydrofuran (THF), dioxane,ethylene glycol dimethylether, dimethylformamide (DMF),N-methylpyrrolidinone (NMP), or dimethylsulfoxide (DMSO), or acombination of two or more of these solvents. The temperature of thereaction may vary from about −20° C. to ambient temperature.

Scheme D illustrates another method for preparing compounds of theformula 1A. Addition of a compound of the formula 9 to a compound of theformula 7 provides the corresponding compound of formula 10. Thisreaction is generally conducted in the presence of a base such aspotassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassiumhydride, lithium diisopropylamide, lithium bis(trimethylsilyl)amide,potassium bis(trimethylsilyl)amide, or sodium bis(trimethylsilyl)amide.Suitable solvents for this reaction include THF, dioxane, ethyleneglycol dimethylether, DMF, NMP, and DMSO, or a combination of two ormore of these solvents. The reaction temperature can range from about−78° C. to about ambient temperature, and is preferably from about −20°to about 0° C. Compounds of the formula 10 can be debenzylated usingmild catalytic hydrogenation methods to provide the correspondingcompounds of formula 1A(1). For example, the hydrogenation can beconducted using 5% palladium on activated carbon in a solvent such asmethanol, ethanol, or THF, or a combination of two or more of thesesolvents, for a period of about 1 hour. More exhaustive catalytichydrogenation of compounds of the formula 10 or 1A (when G is compatiblewith the hydrogenation conditions) provides compounds of formula 1A(2).For example, the hydrogenation can be conducted using 5 to 20% palladiumon activated carbon in a solvent such as methanol, ethanol, THF, aceticacid, or DMF, or a combination of two or more of these solvents, for aperiod of about 5 hours to about 48 hours, preferably for about 12 to 24hours.

Compounds of the formula 1A wherein D is N can also be prepared byreacting a compound of the formula 11, depicted below

wherein n is an integer from 1 to 4, with a compound of the formulaG—L², wherein L² is bromo, iodo, chloro or triflate (OTf), underBuchwald palladium catalyzed amination conditions, as described in J.Org. Chem., 2000, 65, 1158). For example, the coupling can be conductedusing a catalytic amount of palladium acetate (Pd(OAc)₂) ortris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃) and a phosphineligand such as 2-dicyclohexylphosphino-2′(N,N-dimethylamino)biphenyl,2-(dicyclohexylphosphino)biphenyl, 2-(di-tert-butylphosphino)biphenyl or2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP) in the presenceof a base such as cesium carbonate, sodium tert-butoxide or potassiumphosphate (K₃PO₄), in a solvent such as toluene, dioxane, or ethyleneglycol dimethyl ether (DME). The temperature of the reaction may varyfrom about ambient temperature to about the reflux temperature of thesolvent used.

Scheme E illustrates a method for preparing compounds of the formula 1wherein A is —(CH₂)_(m)CH₂—, optionally substituted as described in thedefinition of formula 1 above, (compounds of the formula 1 B). Referringto Scheme E, compounds of the formula 5 can be reacted with achloroalkenylboronic acid of the formula Cl(CH₂)_(n)CH═CHB(OH)₂, whereinn is an integer from 1 to 4, under palladium-catalyzed Suzukicross-coupling conditions (Chem. Rev. 1995, 95, 2457), to give thecorresponding compounds of formula 12. For example, the coupling can beconducted using a catalytic amount oftetrakis(triphenylphosphine)-palladium(0) in the presence of a base suchas aqueous sodium carbonate, sodium hydroxide, or sodium ethoxide, in asolvent such as THF, dioxane, ethylene glycol dimethylether, ethanol(EtOH) or benzene. The temperature of the reaction may vary from aboutambient temperature to about the reflux temperature of the solvent used.The resulting compounds of the formula 12 are then reacted with aG-substituted piperazine or piperidine, as depicted in Scheme E, toyield the corresponding compounds of formula 13. This reaction istypically run in the presence of a base such as potassium carbonate,sodium carbonate, cesium carbonate, triethylamine ordiisopropylethylamine. Typical solvents include acetonitrile, water,THF, dioxane, acetone, methyl isobutyl ketone, benzene or toluene, or acombination of two or more of these solvents. Inorganic salts such assodium or potassium iodide may be employed as catalysts in the reaction.The temperature of the reaction can range from about ambient temperatureto about the reflux temperature of the solvent. The reaction may also beconducted under microwave irradiation. Hydrogenation of compounds of theformula 13, using methods well known to those of skill in the art,yields the desired compounds of formula 1B. For example, thehydrogenation reaction can be conducted using catalytic Raney-nickel ina solvent such as ethanol, methanol, or THF, or a combination of two ormore of these solvents, at a hydrogen pressure from about 1 atmosphereto about 5 atmospheres, preferably at about 1 atmosphere.

Compounds of the formula 5 wherein R¹³ is chloro, fluoro or bromo, and Xis double bonded to Y can be prepared by diazotization of the analogouscompounds wherein R¹³ is replaced by an amino group with sodium nitrite,followed by in situ trapping of the diazonium ion with a halogen sourcesuch as hydrogen fluoride, hydrogen bromide tetrafluoroboric acid(HBF₄), hydrogen chloride, copper(l) chloride, hydrogen bromide orcopper(l) bromide. For example, the reaction to form a compound of theformula 5 wherein R¹³ is chloro can be conducted in concentratedhydrochloric acid with the optional addition of copper(l) chloride at atemperature of about −20° C. to about ambient temperature. In the caseof deaminative fluorinations, the reaction can be enhanced by employinga base such as pyridine, as described in Tetrahedron, 1996, 52, 23.Compounds of the formula 5 wherein R¹³ is chloro, fluoro or bromo, and Xis single bonded to Y can be prepared using a similar method wherein theaminated starting material described above is first subjected tohydrogenation using methods well known to those of skill in the art, forexample, using 5 to 20% palladium on activated carbon in a solvent suchas acetic acid, 1N to 6N hydrochloric acid, or DMF, for a period fromabout 12 hours to about 24 hours.

Compounds of the formula 5 wherein R¹ is other than hydrogen can beprepared from the analogous compounds wherein R¹ is hydrogen by reactingsuch analogous compounds with a compound of the formula R¹ Br in thepresence of a base such as potassium t-butoxide, sodium hydride, lithiumdiisopropylamide or lithium bis(trimethylsilyl)amide, in a solvent suchas THF, dioxane, ethylene glycol dimethylether, DMF, or DMSO, or acombination of two or more of these solvents. Suitable temperatures forthis reaction range from about 0° C. to about the reflux temperature ofthe solvent.

Scheme F illustrates an alternative method for preparing compounds ofthe formula 5A (1) (J. Org. Chem. 1990, 55, 4744). (Compounds of theformula 5A (1) are compounds of the formula 5 wherein X is CR³, Y is CR²and there is a double bond between X and Y). Ortho metalation ofcompounds of the formula 14 and subsequent treatment with electrophileshaving the formula shown in Scheme F results in compounds of the formula15. Condensation of compounds of the formula 15 with the enolates of thealkyl esters having the formula shown in Scheme F provides thecorresponding compounds of formula 16. Refluxing compounds of theformula 16 in aqueous acid such as 3N hydrochloric acid, with theoptional use of a co-solvent such as dioxane, generates thecorresponding compounds of formula 5A (1).

Scheme G illustrates another method for preparing compounds of theformula 2A-1. Addition of a suitably mono-protected diol, where n is aninteger between 1 and 4 and P is tetrahydropyranyl (THP), benzyl, ortert-butyldimethysilyl, to compounds of the formula 17 providescompounds of the formula 18. The reaction is conducted in the presenceof a base such as potassium tert-butoxide, sodium tert-butoxide, sodiumhydride, potassium hydride, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or sodiumbis(trimethylsilyl)amide. The solvents used may be THF, dioxane,ethylene glycol dimethylether, DMF, NMP, or DMSO or a combination of twoor more of these solvents. The temperature of the reaction may vary fromabout 0° C. to about the reflux temperature of the solvent.

Alternatively, compounds of the formula 18 can be prepared fromcompounds of the formula 17 according to the method described in SchemeF for the preparation of compounds of the formula 15.

Condensation of compounds of the formula 18 with the enolates of theesters having the formula shown in Scheme G provides α-hydroxy esterintermediates, which are treated with an aqueous acid such as 3Nhydrochloric acid, with the optional use of a co-solvent such asdioxane, at temperatures varying from about ambient temperature to aboutthe reflux temperature of the solvent, to generate compounds of theformula 2A-1.

Alternatively, Horner-Wadsworth-Emmons reaction of compounds of theformula 18 with ketophosphonates having the formula shown in Scheme G,in the presence of a base such as sodium hydride, sodium ethoxide, orbutyl lithium, in a solvent such as THF, DMSO, dioxane, ethylene glycoldimethylether, ethanol, or benzene, or a combination of two or more ofthese solvents, to give the corresponding intermediate α,β-unsaturatedesters. This reaction can also be conducted using lithium chloride and abase, such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or triethylamine,in a solvent such as acetonitrile or THF. The intermediateα,β-unsaturated esters are then treated with aqueous hydrochloric acidwith the optional use of a co-solvent such as dioxane to provide thedesired compounds of the formula 2A-1. The temperature of this reactionmay vary from about ambient temperature to about the reflux temperatureof the solvent.

Scheme H illustrates a method for preparing compounds of the formula5B-1, 5B-2 and 5B-3. Ortho metalation of compounds of the formula 14, asdescribed in Scheme F, and subsequent treatment with 3-oxopropionic acidesters of the formula shown in Scheme H above provides the correspondingcompounds of formula 19. The reaction can be conducted in a solvent suchas tetrahydrofuran at temperatures ranging from about −78° C. to aboutambient temperature, preferably from about −78° C. to about −20° C.Refluxing compounds of the formula 19 in an aqueous acid such as 3Nhydrochloric acid, with the optional use of a co-solvent such asdioxane, generates the corresponding compounds of formula 5B-1.Compounds of the formula 5B-2 can be prepared by treating thecorresponding compounds of the formula 5B-1 with triethylsilane intrifluoroacetic acid at a temperature from about room temperature to thereflux temperature of the solvent. Compounds of the formula 5B-3 can beprepared by treating compounds of the formula 5B-1 with an oxidizingagent such as Dess Martin periodinane, IBX or PCC at about ambienttemperature in a solvent such as dichloromethane, dichloroethane, THF orDMSO, or a combination of two or more of these solvents.

Scheme I illustrates a method for preparing compounds of the formula 5B(4) (see PCT Patent Application WO 02/056882). Alkylation of compoundsof the formula 20 with an ester of the formula shown in Scheme I (L=Br,I, Cl, OMs, OTs) yields the corresponding compounds of formula 21. Thisreaction is typically run in the presence of a base such as potassiumcarbonate or sodium hydride, in a solvent such as acetonitrile, THF,dioxane, acetone, methyl isobutyl ketone, benzene, toluene or DMF, or acombination of two or more of these solvents. The temperature of thereaction may vary from about ambient temperature to about the refluxtemperature of the solvent. The nitro group of compounds of the formula21 can be reduced with iron powder and acetic acid, with or without theaddition of a solvent such methanol or water, at temperatures from aboutroom temperature to about the reflux temperature of the solvent mixtureused. These conditions also result in ring closure to yield compounds ofthe formula 5B (4).

Scheme K illustrates a method for preparing compounds of the formula5B-5. Compounds of the formula 22 can be heated with liquid ammonia in asealed reaction vessel at temperatures of about 40° C. to about 100° C.,in a solvent such as THF, to yield compounds of the formula 23.Reduction of the ester of compound 23 to the corresponding alcohol,using lithium aluminum hydride, under conventional conditions well knownto those of skill in the art, followed by oxidation of the alcohol withan oxidizing agent such as barium manganate, manganese dioxide, IBX,Dess Martin periodinane, or PCC, in a solvent such as dichloromethane,THF, or DMSO, or a combination of two or more of these solvents, yieldsthe corresponding aldehydes of formula 24. Compounds of the formula 24can then be reacted with (carbethoxymethylene)triphenylphosphorane or asimilar Wittig reagent in a solvent such as dichloromethane, chloroform,THF, benzene or toluene, at a temperature from about room temperature toabout the reflux temperature of the solvent, to give the correspondingcompounds of formula 25. In the case of barium manganate, the oxidationand the Wittig reaction can be carried out using a one-pot procedure (J.Org. Chem. 1998, 63, 4489). Hydrogenation of compounds of the formula25, using methods known to those skilled in the art, for example, asdescribed above, preferably using palladium on barium sulfate in asolvent such as THF, provides the corresponding amino esters. Theresulting amino esters can be cyclized to give compounds of the formula5B(5) by heating at a temperature from about 50° C. to about the refluxtemperature of the solvent, in a solvent such as ethanol, methanol orisopropanol, preferably with a catalytic amount of acid (i.e., TsOH) orbase (i.e., DBU).

Scheme L illustrates an alternative method for preparing compounds ofthe formula 2A-2 and 2B-1. Compounds of the formula 26 can be preparedby reacting compounds of the formula 5A-2 with benzyl alcohol in thepresence of a base such as such as potassium tert-butoxide, sodiumtert-butoxide, sodium hydride, potassium hydride, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, potassiumbis(trimethylsilyl)amide, or sodium bis(trimethylsilyl)amide. Thesolvents used may be tetrahydrofuran, dioxane, ethylene glycoldimethylether, dimethylformamide, N-methylpyrrolidinone,dimethylsulfoxide, or a combination of two of the formerly mentionedsolvents. The temperature of the reaction may vary from ambient to thereflux temperature of the solvent used. Compounds of the formula 26 canbe reacted with a suitably mono-protected diol, preferably P=Bn, underMitsunobo conditions to give compounds of the formula 27. Typicalreaction conditions employ diethyldiazodicarboxylate (DEAD) andtriphenylphosphine in a solvent such as tetrahydrofuran. Compounds ofthe formula 27 can be hydrogenated to give compounds of the formula 2A-2and 2B-1 following methods described in Scheme C for the hydrogenationof compounds of the formula 8.

Scheme M illustrates an alternative method for preparing compounds ofthe formula 2B-2. Addition of a suitably mono-protected diol, where n isan integer between 1 and 4 and P is tetrahydropyranyl (THP), benzyl, ortert-butyldimethysilyl (TBS), to compounds of the formula 28 providesthe corresponding compounds of formula 29. This reaction is typicallyconducted in the presence of a base such as potassium tert-butoxide,sodium tert-butoxide, sodium hydride, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or sodiumbis(trimethylsilyl)amide, in a solvent such as THF, dioxane, or ethyleneglycol dimethylether, preferably THF. The temperature of the reactionmay vary from about −78° C. to about room temperature. Compounds of theformula 29 can be reacted with sodium azide in solvents such as DMF, NMPor DMSO, or a combination of two or more of these solvents, to providecompounds of the formula 30. The temperature of the reaction may varyfrom about room temperature to about the reflux temperature of thesolvent, and is preferably about 70° C. The azide of compounds of theformula 30 can be reduced to an amine using conventional reducing agentsknown to those skilled in the art, preferably usinghexamethyldisilthiane [(Me₃Si)₂S] in a solvent such as methanol orethanol. Subsequent reduction of the cyano group to an aldehyde usingdiisobutylaluminum hydride in a solvent such as THF at about 0° C.provides compounds of the formula 31. Compounds of the formula 31 can bereacted with (carbethoxymethylene)triphenylphosphorane or a similarWittig reagent in a solvent such as dichloromethane, chloroform, THF,benzene or toluene, or a mixture of two or more of these solvents, atabout room temperature to about the reflux temperature of the solvent,to give compounds of the formula 32. Compounds of the formula 32 can behydrogenated using methods known to those skilled in the art, using, forexample, palladium on activated carbon, palladium on barium sulfate, orRaney-nickel, in a solvent such as methanol, ethanol, THF, or acombination of two of the formerly mentioned solvents. The resultingamino esters can be cyclized to give the corresponding compounds of theformula 2B-2 by heating at a temperature from about 50° C. to about thereflux temperature of the solvent, in a solvent such as ethanol,methanol or isopropanol, or a mixture of two or more of these solvents.Preferably, a catalytic amount of acid (i.e., TsOH) or base (i.e., DBU)is used.

Scheme N illustrates a method for preparing compounds of the formula2B(3). The corresponding compounds of formula 2B are halogenatedregioselectively with N-bromosuccinamide, N-chlorosuccinamide, orN-iodosuccinamide in DMF at temperatures from about room temperature toabout 80° C. to provide compounds of the formula 2B-3 (J. Med. Chem.2003, 46, 702).

Scheme O illustrates a method for preparing compounds of the formulaIB-2. Compounds of the formula 15 can be reacted withchloro-alkenylboronic acids (n=1 to 3) under palladium-catalyzed Suzukicross-coupling conditions as 15 described in Scheme E to give compoundsof the formula 33. Subsequent reaction with the G-substitutedpiperazines or piperidines of the formula shown in Scheme O according tothe methods described in Scheme E provide the corresponding compounds offormula 34. Compounds of the formula 34 may be hydrogenated in thepresence of a catalyst such as Raney-nickel in a solvent such asethanol, methanol, tetrahydrofuran, or a combination of two of theformerly mentioned solvents. Subsequent removal of the pivaloyl groupunder acidic conditions, preferably with 3N aqueous hydrochloric acid attemperatures of about room temperature to about the reflux temperatureof the solvent provides compounds of the formula 35. Compounds of theformula 35 can be reacted with Grignard reagents such as alky magnesiumbromides in solvents such as tetrahydrofuran, diethyl ether, toluene, ora combination of two of the formerly mentioned solvents at temperaturesof about −78° C. to room temperature to give the corresponding alcohols.Subsequent treatment with reagents such as phosgene, carbonyldiimidazole(CDI), 4-nitrophenyl chloroformate, methyl chloroformate, or phenylchloroformate, with or without a base such as triethylamine, pyridine,potassium bicarbonate, or potassium carbonate in solvents such astetrahydrofuran, methyl tert-butyl ether (MTBE), water, toluene,hexanes, heptane or a combination of two of the formerly mentionedsolvents gives compounds of the formula IB-2 (J Org. Chem. 1998, 63,8536).

The preparation of other compounds of the formula 1 not specificallydescribed in the foregoing experimental section can be accomplishedusing combinations of the reactions described above that will beapparent to those skilled in the art.

In each of the reactions discussed or illustrated above, pressure is notcritical unless otherwise indicated. Pressures from about 0.5atmospheres to about 5 atmospheres are generally acceptable, and ambientpressure, i.e., about 1 atmosphere, is preferred as a matter ofconvenience.

The compounds of the formula 1 and the intermediates shown in the abovereaction schemes can be isolated and purified by conventionalprocedures, such as recrystallization or chromatographic separation.

The compounds of the formula 1 and their pharmaceutically acceptablesalts, can be administered to mammals via either the oral, parenteral(such as subcutaneous, intravenous, intramuscular, intrasternal andinfusion techniques), rectal, buccal or intranasal routes. In general,these compounds are most desirably administered in doses ranging fromabout 3 mg to about 600 mg per day, in single or divided doses (i.e.,from 1 to 4 doses per day), although variations will necessarily occurdepending upon the species, weight and condition of the patient beingtreated and the patient's individual response to said medicament, aswell as on the type of pharmaceutical formulation chosen and the timeperiod and interval at which such administration is carried out.However, a dosage level that is in the range of about 10 mg to about 100mg per day is most desirably employed. In some instances, dosage levelsbelow the lower limit of the aforesaid range may be more than adequate,while in other cases still larger doses may be employed without causingany harmful side effects, provided that such higher dose levels arefirst divided into several small doses for administration throughout theday.

The novel compounds of the present invention may be administered aloneor in combination with pharmaceutically acceptable carriers or diluentsby any of the routes previously indicated, and such administration maybe carried out in single or multiple doses. More particularly, the noveltherapeutic agents of this invention can be administered in a widevariety of different dosage forms, i.e., they may be combined withvarious pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, troches, hard candies, suppositories,jellies, gels, pastes, ointments, aqueous suspensions, injectablesolutions, elixirs, syrups, and the like. Such carriers include soliddiluents or fillers, sterile aqueous media and various non-toxic organicsolvents, etc. Moreover, oral pharmaceutical compositions can besuitably sweetened and/or flavored. In general, the weight ratio of thenovel compounds of this invention to the pharmaceutically acceptablecarrier will be in the range from about 1:6 to about 2:1, and preferablyfrom about 1:4 to about 1:1.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch (and preferably corn, potato or tapioca starch), alginicacid and certain complex silicates, together with granulation binderslike polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in gelatin capsules;preferred materials in this connection also include lactose or milksugar as well as high molecular weight polyethylene glycols. Whenaqueous suspensions and/or elixirs are desired for oral administration,the active ingredient may be combined with various sweetening orflavoring agents, coloring matter or dyes, and, if so desired,emulsifying and/or suspending agents as well, together with suchdiluents as water, ethanol, propylene glycol, glycerin and various likecombinations thereof.

For parenteral administration, solutions of a compound of the presentinvention in either sesame or peanut oil or in aqueous propylene glycolmay be employed. The aqueous solutions should be suitably buffered(preferably pH greater than 8) if necessary and the liquid diluent firstrendered isotonic. These aqueous solutions are suitable for intravenousinjection purposes. The oily solutions are suitable for intra-articular,intra-muscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well known to those skilled in theart.

This invention relates to methods of treating anxiety, depression,schizophrenia and the other disorders referred to in the description ofthe methods of the present invention, wherein a novel compound of thisinvention and one or more of the other active agents referred to above(e.g., an NK1 receptor antagonist, tricyclic antidepressant, 5HT1Dreceptor antagonist, or serotonin reuptake inhibitor) are administeredtogether, as part of the same pharmaceutical composition, as well as tomethods in which such active agents are administered separately as partof an appropriate dose regimen designed to obtain the benefits of thecombination therapy. The appropriate dose regimen, the amount of eachdose of an active agent administered, and the specific intervals betweendoses of each active agent will depend upon the subject being treated,the specific active agent being administered and the nature and severityof the specific disorder or condition being treated. In general, thenovel compounds of this invention, when used as a single active agent orin combination with another active agent, will be administered to anadult human in an amount from about 3 mg to about 300 mg per day, insingle or divided doses, preferably from about 10 to about 100 mg perday. Such compounds may be administered on a regimen of up to 6 timesper day, preferably 1 to 4 times per day, especially 2 times per day andmost especially once daily. Variations may nevertheless occur dependingupon the species of animal being treated and its individual response tosaid medicament, as well as on the type of pharmaceutical formulationchosen and the time period and interval at which such administration iscarried out. In some instances, dosage levels below the lower limit ofthe aforesaid range may be more than adequate, while in other casesstill larger doses may be employed without causing any harmful sideeffect, provided that such larger doses are first divided into severalsmall doses for administration throughout the day.

A proposed daily dose of a 5HT reuptake inhibitor, preferablysertraline, in the combination methods and compositions of thisinvention, for oral, parenteral or buccal administration to the averageadult human for the treatment of the conditions referred to above, isfrom about 0.1 mg to about 2000 mg, preferably from about 1 mg to about200 mg of the 5HT reuptake inhibitor per unit dose, which could beadministered, for example, 1 to 4 times per day. A proposed daily doseof a 5HT1D receptor antagonist in the combination methods andcompositions of this invention, for oral, parenteral, rectal or buccaladministration to the average adult human for the treatment of theconditions referred to above, is from about 0.01 mg to about 2000 mg,preferably from about 0.1 mg to about 200 mg of the 5HT1receptorantagonist per unit dose, which could be administered, for example, 1 to4 times per day.

For intranasal administration or administration by inhalation, the novelcompounds of the invention are conveniently delivered in the form of asolution or suspension from a pump spray container that is squeezed orpumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch. Formulations of the active compounds of thisinvention for treatment of the conditions referred to above in theaverage adult human are preferably arranged so that each metered dose or“puff” of aerosol contains 20 μg to 1000 μg of active compound. Theoverall daily dose with an aerosol will be within the range 100 μg to 10mg. Administration may be several times daily, for example 2, 3, 4 or 8times, giving for example, 1, 2 or 3 doses each time.

The ability of the novel compounds of this invention to bind to thedopamine D₂ receptor can be determined using conventional radioligandreceptor binding assays. All receptors can be heterologously expressedin cell lines and experiments conducted in membrane preparations fromthe cell lines using procedures outlined below. IC₅₀ concentrations canbe determined by nonlinear regression of concentration-dependentreduction in specific binding. The Cheng-Prussoff equation can be usedto convert the IC₅₀ to Ki concentrations.

Dopamine D₂ Receptor Binding Assay:

[³H]Spiperone binding to a membrane preparation from CHO-hD₂L cells iscarried out in 250 μl of 50 mM Tris-HCl buffer containing 100 mM NaCl, 1mM MgCl₂ and 1% DMSO at pH 7.4. Duplicate samples containing (in orderof addition) the test compounds, 0.4 nM [³H]spiperone and approximately12 μg protein are incubated for 120 minutes at room temperature. Boundradioligand is separated by rapid filtration under reduced pressurethrough Whatman GF/B glass fiber filters previously treated with 0.3%polyethyleneimine. Radioactivity retained on the filter is determined byliquid scintillation spectrophotometry.

Title compounds of the Examples, below, were tested using the aboveassay, in which specific binding determined in the presence of 1 mMhaloperidol was 95%. All of the title compounds exhibited Ki values lessthan or equal to 75 nM (see Tables 1 and 2, below). Preferredembodiments of compounds of the present invention preferably exhibit Kivalues of no more than 100 nM, more preferably no more than 50 nM, evenmore preferably no more than 25 nM, most preferably no more than 10 nM.

D₂ intrinsic activity of title compounds of the Examples, below, wasdetermined using the [³H]thymidine uptake assay described below.

[³H]Thymidine Uptake Assay for D₂ Intrinsic Activity

Cells are serum deprived by washing twice with 200 μl of serum-freemedia. 90 μl serum-free media was added to each well. The plates wareincubated for two to three hours. 10 μl of serum-containing media, as apositive control, vehicle (serum-free media), negative control (anantagonist) or test compounds and standards (10 μl of a 10 μM solutionfor a final concentration of 1 μM) in serum-free media were added towells. The plates are returned to the incubator. Eighteen hours later[³H]thymidine is added (0.5 μCi/well in 10 μl of serum-free media) andthe plates are returned to the incubator. Four hours later trypsin(0.25%) is added (100 μl/well). The plates are returned to theincubator, once again. One hour later the assay is terminated by rapidfiltration through Whatman GF/C glass fiber filters. Filters are washedfour times with 500 ml of 50 mM Tris-HCl pH 7.0 buffer, for example,using a Brandel MLR-96T cell harvester. Radioactivity remaining on thefilters are estimated, for example, with a Wallac 1205 Betaplate liquidscintillation counter (50% efficiency). Intrinsic activity is defined astotal uptake (1 μM Quinpirole) minus serum-free media (no uptake). Testcompounds are compared to 1 μM Quinpirole (full DA agonist), which wasclassified as 100% intrinsic activity. All assays are preferablyperformed in triplicate, with each drug occupying one full column (8wells) per plate.

Compounds of the present invention preferably exhibit at least 1% to upto 90% intrinsic activity, more prefeferably at least 10% to up to 90%activity, more preferably at least 10% to up to 80% activity, morepreferably at least 20% to up to 60% intrinsic activity, even morepreferably at least 30% to up to 50% intrinsic activity.

Each of the title compounds produced as described in the Examples,below, were also tested using the above assay. All of the titlecompounds tested in this assay exhibited an intrinsic activity between 2and 83 percent. See Tables 1 and 2, below, for results obtained fromeach of the compounds tested. TABLE 1 Example D₂ Ki (nM) D₂ IntrinsicActivity (%) A1 1.0 30 A2 1.0 29 A3 3.0 35 A4 2.5 28 A5 2.5 29 A6 1.0 31A7 1.0 15 A8 10.0 7 A9 5.5 9 A10 5.7 31 A11 6.5 6 A12 2.0 11 A13 11.4 21A14 5.5 7 A15 4.5 4 A16 3.5 16 A17 1.0 15 A18 7.7 NOT TESTED A19 19.5 10A20 0.7 19 A21 6.7 NOT TESTED A22 4.5 36 A23 14.9 NOT TESTED A24 16.5 40A25 1.0 27 A26 1.0 33 A27 1.4 38 A28 3.5 2 A29 2.5 20 A30 15.5 11 A312.0 26 A32 2.0 7 A33 15.5 31 A34 0.5 8 A35 0.3 24 A36 5.0 38 A37 2.2 46A38 6.0 23 A39 7.9 56 A40 12.0 32 A41 9.1 28 A42 4.9 28 A43 52.0 75 A4422.2 51 A45 2.8 34 A46 2.0 41 A47 75.9 NOT TESTED A48 0.8 34 A49 1.4 21A50 0.8 14 A51 0.4 20 A52 2.0 32 A53 5.3 NOT TESTED A54 0.6 NOT TESTEDA55 0.2 NOT TESTED A56 2.5 29 A57 9.4 NOT TESTED A58 30.4 48 A59 4.5 30A60 1.0 18 A61 2.2 NOT TESTED A62 0.9 27 A63 35.0 4 A64 3.5 36 A65 1.036 A66 2.0 49 A67 1.0 19 A68 6.0 17 A69 2.0 10 A70 1.1 14 A71 1.6 3 A723.5 NOT TESTED A73 1.0 23 A74 4.0 37 A75 23.8 36 A76 8.7 16 A77 10.8 36A78 1.4 24 A79 15.0 24 A80 23.5 30 A81 24.7 4 A82 28.1 27 A83 2.5 36 A843.0 11 B1 1.0 19 B2 2.5 22 B3 3.9 8 B4 1.4 22 B5 3.0 2 B6 1.0 16 B7 5.028 B8 2.0 17 B9 1.7 23 B10 1.2 34 B11 1.4 31 B12 4.9 38 B13 11.2 45 B146.5 37 B15 2.5 17 B16 2.5 41 B17 1.7 43 B18 3.0 32 B19 4.6 NOT TESTEDB20 13.0 NOT TESTED B21 6.7 NOT TESTED B22 1.0 36 B23 2.5 15 B24 4.6 10B25 2.2 43 B26 11.5 23 B27 9.8 47 B28 1.4 31 B29 1.0 32 B30 28.0 83 B3169.5 76 B32 <2 19 B33 2.0 26 B34 0.7 14 B35 0.4 20 B36 3.0 39 B37 4.0NOT TESTED B38 0.6 NOT TESTED B39 1.0 NOT TESTED B40 1.4 36 B41 4.2 NOTTESTED B42 8.5 37 B43 3.0 18 B44 0.7 27 B45 0.6 NOT TESTED B46 1.0 29B47 0.3 44 B48 1.0 19 B49 0.9 50 B50 1.0 51 B51 3.5 36 B52 3.5 17 B531.1 26 B54 2.8 15 B55 1.0 NOT TESTED B56 2.0 28 B57 4.1 21 B58 12.5 42B59 5.1 37 B60 1.6 28 B61 23.9 18 B62 1.0 21 B63 47.9 18 B64 17.0 27 B659.2 10 B66 29.2 33 B67 2.5 39 B68 4.5 17 C1 6.6 43 C2 4.7 24 C3 6.8 22C4 54.1 2 C5 1.4 40 C6 2.0 44 C7 2.0 46 C8 1.4 33 C9 2.6 34 C10 7.0 5C11 16.4 7 C12 13.5 12 C13 2.0 14 C14 65.5 10 C15 32.0 8 C16 46.7 34 C1720.5 21 C18 7.1 34 C19 10.4 13 C20 2.0 33 D1 1.0 31 D2a 2.9 20 D2b 2.024 D3 4.5 15 D4 2.0 16 D5 1.8 15 D6a 2.5 17 D6b 3.0 24 D7 3.0 15 D8 2.28 D9 1.0 15 D10 0.9 22 D11 1.4 30 D12 5.0 3 D13 2.8 19 D14 0.4 3 D15 0.625 D16 3.0 31 D17 3.9 29 D18 4.7 37 D19 3.2 39 D20 2.0 44 D21 12.5 24D22 5.2 42 D23 6.9 33 D24 13.4 32 D25 1.6 31 E1 2.0 32 E2 1.3 22 E3 1.031 E4 2.2 38 E5 2.0 21 E6 3.5 32 E7 6.3 19 E8 1.4 26 E9 1.4 34 E10 1.031 E11 1.0 19 E12 1.0 39 E13 5.0 11 E14 28.5 36 E15 39.8 20 F1 0.6 8 F21.0 30 F3 0.8 15 F4 1.4 23 F5 1.0 32 F6 0.6 37 F7 0.5 11 F8 1.0 15 F93.9 11 G1 7.5 27 G2 3.9 6 G3 1.4 25 G4 0.7 NOT TESTED G5 0.6 NOT TESTEDG6 66.7 NOT TESTED G7 0.8 NOT TESTED G8 1.0 NOT TESTED H1 1.0 28 H2 1.022 H3 1.8 25 H4 4.9 38 H5 3.0 34 H6 1.0 42 H7 8.8 46 H8 1.3 NOT TESTEDH9 1.0 NOT TESTED H10 3.0 44 H11 0.4 23 H12 1.0 34 H13 15.4 36 H14 9.333 I1 5.0 17 I2 9.0 37 I3 14.5 33 I4 NOT TESTED NOT TESTED I5 13.9 23 I61.0 24 I7 7.4 37 I8 5.9 25 I9 4.5 19 I10 9.5 21 I11 8.7 19 I12 NOTTESTED NOT TESTED I13 2.0 19 I14 3.5 24 I15 2.5 20 I16 2.1 27 I17 1.0 32I18 1.6 54 I19 7.5 22

TABLE 2 Example D₂ Ki (nM) D₂ Intrinsic Activity (%) A1′ 0.4 73 A2′ 1.421 A3′ 1.0 37 A4′ 1.0 18 A5′ 2.2 31 A6′ 2.0 42 A7′ 4.0 34 A8′ 1.4 30 A9′1.0 30 A10′ 0.4 NOT TESTED A11′ 3.0 17 A12′ 2.8 NOT TESTED A13′ 0.7 14A14′ 3.0 NOT TESTED A15′ NOT TESTED NOT TESTED A16′ 2.5 15 A17′ 1.0 15A18′ 1.4 13 A19′ 1.4 40 A20′ 65.1 NOT TESTED A21′ 1.0 24 A22′ 0.7 NOTTESTED A23′ 1.1 39 A24′ 2.0 6 A25′ 1.4 36 A26′ 12.5 12 A27′ 0.5 21 A28′0.3 21 A29′ 7.4 33 A30′ 8.9 41 A31′ 0.6 NOT TESTED A32′ 28.0 27 A33′17.3 18 A34′ 1.0 38 A35′ 1.4 20 A36′ 0.6 62 A37′ 1.6 45 A38′ 1.0 20 A39′0.4 NOT TESTED A40′ 1.0 30 A41′ 1.0 32 A42′ 0.7 NOT TESTED A43′ 25.2 32A44′ 18.6 29 A45′ 4.2 NOT TESTED A46′ 3.2 NOT TESTED A47′ 15.9 32 A48′7.4 34 A49′ 7.5 38 B1′ 1.0 22 B2′ 1.0 33 B3′ 2.0 50 B4′ 1.0 28 B5′ 0.3NOT TESTED B6′ 1.0 33 B7′ 1.0 48 B8′ 1.0 21 B9′ 1.0 40 B10′ 1.0 22 B11′1.0 21 B12′ 2.0 24 B13′ 2.0 33 B14′ 2.0 NOT TESTED B15′ 9.4 NOT TESTEDB16′ 1.1 4 B17′ 1.4 NOT TESTED B18′ 1.4 NOT TESTED B19′ 1.0 NOT TESTEDB20′ 1.0 16 B21′ 1.0 18 B22′ 1.0 12 B23′ 5.5 21 B24′ 0.8 42 B25′ 1.0 21B26′ 1.2 26 B27′ 17.9 34 B28′ 7.5 44 B29′ 31.9 26 B30′ 1.0 42 B31′ 0.6NOT TESTED B32′ 1.4 NOT TESTED B33′ 4.2 NOT TESTED B34′ 0.7 35 B35′ 0.4NOT TESTED B36′ 12.9 36 B37′ 3.2 39 B38′ 3.0 46 B39′ 5.7 29 B40′ 3.9 49B41′ 0.8 NOT TESTED C1′ 6.2 38 C2′ 1.9 22 C3′ 7.0 19 C4′ 18.4 21 C5′ 3.023 C6′ 1.4 24 D1′ 2.0 24 D2′ 5.0 40 E1′ 1.0 12 E2′ 0.5 9 E3′ 0.7 8 E4′0.4 26 F1′ 0.7 NOT TESTED F2′ 2.4 NOT TESTED F3′ 10.1 NOT TESTED F4′ 1.0NOT TESTED F5′ 0.8 NOT TESTED G1′ 10.0 20 G2′ 3.5 21 G3′ 17.6 28 G4′ 9.013 G5′ 8.5 7 G6′ 0.7 17 G7′ 1.4 38 G8′ 2.5 32 G9′ 5.5 21 G10′ 1.0 18G11′ 2.0 39 G12′ 3.0 36 G13′ 2.5 NOT TESTED G14′ 15.0 44 G15′ 3.4 41 H1′4.9 22 H2′ 6.9 15 H3′ 2.0 22 H4′ 0.6 21 H5′ 5.5 14 H6′ 6.5 21 H7′ 3.9 17H8′ 3.5 32 H9′ 0.6 31

The following Examples illustrate the preparation of several compoundsof the present invention. Melting points are uncorrected. NMR data arereported in parts per million and are referenced to the deuterium locksignal from the sample solvent. Any reference to a “title compound” inan example, below, refers to the compound named in the title of thatparticular example.

EXAMPLES Example A1 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, 2-Benzyloxy-7-chloro-[1,8]naphthyridine,was produced, as follows. To a solution of benzyl alcohol (5.0 mL, 48.0mmol) in THF (50 mL) cooled to 0° C. was added KOtBu (1M in THF, 46 mL,46.0 mmol). The solution was stirred at 0° C. for 20 min and then addedvia cannula to a suspension of 2,7-dichloro-[1,8]naphthyridine (10.0 g,50.2 mmol, J. Org. Chem. 1981, 46, 833) in DMF (50 mL) and THF (50 mL)cooled to 0° C. The orange suspension was stirred at 0° C. for 15 minand at room temperature for 30 min. The reaction was quenched withsaturated NH₄Cl and H₂O. The mixture was extracted with EtOAc. Theorganic layer was filtered through celite to remove an orange clay-likeprecipitate. The organic layer was washed with H₂O and brine, andconcentrated to give an orange solid. The solid was absorbed onto SiO₂and purified by liquid chromatography (2% EtOAc/48% Hexanes/50% CH₂Cl₂)to give the first intermediate compound as a white solid (6.37 g, 23.5mmol, 51%). MS: APCl: M+1:271.0 (Exact Mass: 270.06).

A second intermediate compound,2-Benzyloxy-7-(4-benzyloxy-butoxy)-[1,8]naphthyridine, was produced, asfollows. To a solution of 4-benzyloxy-1-butanol (4.9 mL, 28.2 mmol, 1.2equiv) in THF (20 mL) cooled to 0° C. was added KO^(t)Bu (1M in THF, 27mL, 27 mmol, 1.15 equiv). The solution was stirred at 0° C. for 20 minand then added via cannula to a suspension of2-benzyloxy-7-chloro-[1,8]naphthyridine (6.35 g, 23.5 mmol), produced asdescribed above, in THF (70 mL), and cooled to 0° C. The reaction becamehomogenous. After 30 min at 0° C., saturated NH₄Cl and H₂O were added toquench the reaction. The mixture was extracted with EtOAc. The organiclayer was washed with saturated NaHCO₃, H₂O and brine, dried over Na₂SO₄and concentrated. The crude was absorbed onto SiO₂ and purified byliquid chromatography (10-15% EtOAc/Hexanes) to give the secondintermediate compound as a yellow oil (4.64 g, 11.19 mmol, 48%). MS:APCl: M+1:415.2 (Exact Mass: 414.19).

A third intermediate compound,7-(4-Hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one, wasproduced, as follows. To a solution of2-benzyloxy-7-(4-benzyloxy-butoxy)-[1,8]naphthyridine (4.64 g, 11.19mmol) in MeOH (100 mL) was added 20% Pd/C (1.5 g) and the mixture washydrogenated for 22 h. The reaction was filtered, concentrated andpurified by liquid chromatography (5% MeOH/CH2Cl2) to give the titlecompound as a white solid (2.44 g, 10.33 mmol, 92%). MS: APCl: M+1:237.1(Exact Mass: 236.12).

The third intermediate compound was also prepared by hydrogenation of7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one (an intermediate inExample B1, below).

A fourth intermediate compound,4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde,was produced using either a Dess-Martin oxidation reaction or a Swernoxidation reaction, as described below.

Dess-Martin oxidation: To a cloudy solution of the Dess-Martinperiodinane (2.80 g, 6.60 mmol, 1.5 equiv) in CH₂Cl₂ (13 mL) was added asolution of 7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one(1.04 g, 4.40 mmol) in CH₂Cl₂ (25 mL) via cannula. The reaction wasstirred at room temperature for 5 h and stored in the freezer overnight.A 1:1 mixture of saturated Na₂S₂O₃ and saturated NaHCO₃ (50 mL) wasadded followed by Et₂O. The mixture was stirred for 10 min and thenextracted with Et₂O/EtOAc (2:1). The organic layer was washed withsaturated NaHCO₃ and brine, dried over Na₂SO₄ and concentrated to givethe fourth intermediate compound as a pale yellow oil (1.06 g, usedcrude in next reaction). MS: APCl: M+1:235.1 (Exact Mass: 234.10).

Swern oxidation: A solution of oxalyl chloride (9.97 mL, 112 mmol) inCH₂Cl₂ was cooled to −70° C. and DMSO (15.6 mL, 220 mmol) was carefullyadded. The solution was stirred at −60° C. for 10 min and then asolution of 7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one(23 g, 97.5 mmol) in DMSO (70 mL) was added dropwise at −50˜−60° C. Thereaction mixture was stirred at −60° C. for 20 min and thentriethylamine (72 mL, 0.513 mol) was added dropwise. The reaction waswarmed to room temp and stirred for 30 min. The mixture was poured intoice-water and the organic phase was separated. The aqueous phase wasextracted with CH₂Cl₂, combined with the organic phase, washed withbrine, dried over Na₂SO₄, and concentrated under vacuum to give thecrude product. Purification by column chromatography (hexane:ethylacetate 2:1) followed by recrystallization provided the fourthintermediate compound (12.7 g, 54.3 mmol, 56%).

In the final step of the synthesis reaction, the title compound,7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-onewas produced as follows: To a solution of4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(1.06 g, crude from previous reaction) was added a solution of2,3-dichlorophenylpiperazine (1.02 g, 4.40 mmol) in dichloroethane (5mL). The solution was stirred for 15 min and NaBH(OAc)₃ (1.21 g, 5.72mmol, 1.3 equiv) was added as a powder. The reaction was stirred at roomtemperature for 3 h and quenched with saturated NaHCO₃ and H₂O. Themixture was extracted with EtOAc. The organic layer was washed withsaturated NaHCO₃, H₂O and brine, dried over Na₂SO₄ and concentrated togive a yellow foam/oil. Purification by liquid chromatography (4%MeOH/CH₂Cl₂) afforded the title compound as a white foam (1.20 g, 2.67mmol, 61 % over 2 steps). The HCl salt was formed by dissolving thetitle compound (800 mg, 1.78 mmol) in Et₂O (20 mL) and CH₂Cl₂ (2 mL)followed by the addition of 1N HCl in Et₂O (1.75 mL). The resultingwhite precipitate was collected by filtration, washed with Et₂O anddried to give a white solid (801 mg). MS: APCl: M+1:449.1 (Exact Mass:448.14).

A variation of this same method was used to produce other compounds asdescribed in examples below, wherein other compounds were substitutedfor 2,3-dichlorophenylpiperazine in the final step of the synthesisprocedure.

Example A2 Synthesis of7-{4-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

7-{4-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-onewas produced according to a process similar to that described in ExampleA1, except that in the final step of the synthesis procedure,2-chloro-3-methylphenylpiperazine hydrochloride (506 mg, 2.05 mmol) wasadded to a solution of4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(approx. 1.9 mmol) in dichloroethane (10 mL), followed by the additionof Et3N (0.53 mL, 3.76 mmol, 2 equiv). NaBH(OAc)₃ (557 mg, 2.63 mmol,1.4 equiv) was added as a powder. The reaction was stirred at roomtemperature (about 25° C.) for 4 hours and worked up as in Example A1.

Purification by liquid chromatography (3-4% MeOH/CH₂Cl₂) gave the titlecompound, as a white foam (430 mg, 1.00 mmol, 53% from the alcohol). Thefoam was dissolved in Et₂O and a white solid crystallized (337 mg). MS:APCl: M+1:429.2 (Exact Mass: 428.20).

Example A3 Synthesis of7-{4-[4-(3-Chloro-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed, exceptthat 2-chloro-3-methylphenylpiperazine was substituted for2,3-dichlorophenylpiperazine in the final stage of the procedure.

Purification by liquid chromatography (3-4% MeOH/CH₂Cl₂) gave the titlecompound as a white foam (558 mg, 1.30 mmol). The foam was dissolved inEt₂O and 1 N HCl in Et₂O (1.3 mL) was added. The resulting whiteprecipitate was collected by filtration, washed with Et₂O and dried togive a white solid (538 mg). MS: APCl: M+1:429.2 (Exact Mass: 428.20).

Example A4 Synthesis of7-{4-[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(2,3-dimethyl-phenyl)-piperazine to give the title compound. MS: APCl:M+1: 409.2 (Exact Mass: 408.25).

Example A5 Synthesis of7-{4-[4-(2-Chloro-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(2-chloro-3-fluoro-phenyl)-piperazine to give the title compound (296mg, 53%). MS: APCl: M+1:433.2 (Exact Mass: 432.17).

Example A6 Synthesis of7-{4-[4-(3-Chloro-2-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed, using1-(3-chloro-2-fluoro-phenyl)-piperazine to give the title compound. MS:APCl: M+1:433.2 (Exact mass: 432.17).

Example A7 Synthesis of7-{4-[4-(2-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate, 1-(2-Chloro-3-trifluoromethyl-phenyl)-piperazine wasproduced as follows: To a stirred solution of trifluoro-methanesulfonicacid 2-chloro-3-trifluoromethyl-phenyl ester (5.0 g, 15.20 mmol) intoluene (50 mL) at room temperature, was added 1-boc-piperazine (3.39 g,18.20 mmol), tris-(dibenzylideneacetone)di-palladium(0) (Pd₂(dba)₃)(3.49 g, 38.10 mmol), tert-2,2′-bis(diphenyl)phosphino-1,1′-binaphthyl(BINAP) (4.27 g, 68.60 mmol) and sodium tert-butoxide (2.04 g, 21.30mmol). The mixture was degassed, filled with N₂, degassed and heated at80° C. for 1.5 h. The mixture was diluted with ethyl acetate, celite wasadded and the mixture was stirred at room temperature for 15 min. It wasfiltered through a pad of silica gel and the pad was washed withadditional amounts of ethyl acetate, The combined solvent was removed invacuo and the residue was purified on a silica gel column usinghexanes-ethyl acetate (5:1) as eluent to give4-(2-chloro-3-trifluoromethyl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (2.30 g, 42%) as an oil. ¹H NMR (400 MHz, CDCl₃): δ7.35 (m, 2H), 7.22 (d, 1H), 3.62 (br s, 4H), 3.05 (br s, 4H), 1.55 (s,9H).

To a stirred solution of4-(2-chloro-3-trifluoromethyl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (2.0 g, 5.49 mmol) in dichloromethane (15 mL) cooled to0 ° C., was added trifluoroacetic acid (6.26 g, 54.90 mmol). Theresulting mixture was stirred at room temperature overnight and thesolvent was removed in vacuo. Ether was added to the residue and thesolid formed was filtered to give the intermediate compound (1.1 g, 55%)named immediately above. ¹H NMR (400 MHz, CDCl₃): 67 9.85 (br s, 1H),7.55 (d, 1H), 7.40 (d, 1H), 7.30 (m, 1H), 7.25 (s, 4H), 7.20 (s, 4H).

The reductive amination procedure from Example A1 was followed using1-(2-chloro-3-trifluoromethyl-phenyl)-piperazine, the intermediatecompound, to give the title compound (0.65 g, 71%). ¹H NMR (400 MHz,CDCl₃): δ 7.65 (s, 1H), 7.40-7.20 (m, 3H), 6.40 (d, 1H), 4.25 (t, 2H),3.15 (br s, 4H), 2.85 (t, 2H), 2.70 (br s, 4H), 2.45 (t, 2H), 1.80 (m,2H), 1.65 (m, 2H). MS ES: m/z 483.01 (M+H)⁺ (Exact mass: 482.17).

Example A8 Synthesis of7-{4-[4-(2,3-Dichloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(2,3-dichloro4-fluoro-phenyl)-piperazine to give the title compound.MS: APCl: M+1:467.1 (Exact mass: 466.13).

Example A9 Synthesis of7-{4-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(2-chloro-4-fluoro-phenyl)-piperazine to give the title compound. MS:APCl: M+1:433.2 (Exact mass: 432.17).

Example A10 Synthesis of7-{4-[4-(2-Chloro-phenyl)-piperazin-1-yl]-butoxy}-3.4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(2-chloro-phenyl)-piperazine to give the title compound. MS: APCl:M+1: 415.2 (Exact mass: 414.18).

Example A11 Synthesis of7-[4-(4-Biphenyl-2-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-biphenyl-2-yl-piperazine to give the title compound. MS: APCl:M+1:457.3 (Exact mass: 456.25).

Example A12 Synthesis of7-{4-[4-(2,5-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(2,5-dichloro-phenyl)-piperazine to give the title compound (0.399 g,82%). MS: APCl: M+1:449.1 (Exact mass: 448.14).

Example A13 Synthesis of7-{4-[4-(2-Chloro-4-fluoro-5-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(2-chloro4-fluoro-5-methyl-phenyl)-piperazine hydrochloride to givethe title compound (0.277 g, 57%). MS: APCl: M+1:447.2 (Exact mass:446.19).

Example A14 Synthesis of7-{4-[4-(5-Chloro-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(5-chloro-2-methyl-phenyl)-piperazine to give the title compound(0.358 g, 77%). MS: APCl: M+1:429.2 (Exact mass: 428.20).

Example A15 Synthesis of7-{4-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(2-chloro-4-fluoro-3-methyl-phenyl)-piperazine hydrochloride to givethe title compound (0.463 g, 96%). MS: APCl: M+1:447.2 (Exact mass:446.19).

Example A16 Synthesis of7-{4-[4-(3-Ethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(3-ethyl-phenyl)-piperazine to give the title compound. MS: APCl:M+1:409.2 (Exact mass: 408.25).

Example A17 Synthesis of7-{4-[4-(3-Chloro-2-methoxy-phenyl)-pirerazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound 1-(3-Chloro-2-methoxy-phenyl)-piperazine, wasproduced as follows. A solution of 2,6-dichloroanisole (1.55 mL, 11.30mmol) in dry toluene (40 mL) was degassed for 10 min by blowing nitrogeninto the solution. This solution was then added via cannula to a flaskcontaining Boc-piperazine 3.16 g, 16.90 mmol), Cs₂CO₃ (5.15 g, 15.80mmol), Pd₂(dba)₃ (414 mg, 0.452 mmol, 4 mol%) and2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (356 mg, 0.904mmol, 8 mol%) under nitrogen. The reaction mixture was heated at 100° C.overnight (16 h). MS showed a small product peak and a largeBoc-piperazine peak. TLC (10% EtOAc/Hex) showed a product spot. Thereaction was allowed to cool to room temperature and Et₂O was added. Themixture was filtered through Celite washing with Et₂O. The filtrate waswashed 3 times with 0.5 M citric acid (to remove excess Boc-piperazine)and once with brine, dried over MgSO₄ and concentrated to give a brownoil. Purification by SiO₂ chromatography (10% EtOAC/Hexanes) gave4-(3-chloro-2-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butylester as a pale yellow solid (278 mg, 8%).

To a solution of 4-(3-chloro-2-methoxy-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (273 mg, 0.835 mmol) in CH₂Cl₂ (4 mL) was addedTFA (4 mL) at RT. The reaction was stirred at room temperature for 1hour and concentrated to give a reddish brown oil. Purification by SiO₂chromatography (10% MeOH/CH₂Cl₂ with 1% NH₄0H) gave1(3-Chloro-2-methoxy-phenyl)-piperazine as a pale yellow solid/oil (137mg, 0.604 mmol, 72%). MS: APCl: M+1:227.1 (Exact Mass: 226.09).

The reductive amination procedure from Example A1 was followed using1-(3-chloro-2-methoxy-phenyl)-piperazine to give the title compound. MS:APCl: M+1:445.2 (Exact Mass: 444.19).

Example A18 Synthesis of7-{4-[4-(3-Methyl-2-phenoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(3-methyl-2-phenoxy-phenyl)-piperazine to give the title compound. MS:APCl: M+1:487.2 (Exact Mass: 486.26).

Example A19 Synthesis of7-{4-[4-(2,3-Dimethoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(2,3-dimethoxy-phenyl)-piperazine to give the title compound. MS:APCl: M+1:441.6 (Exact Mass: 440.24).

Example A20 Synthesis of7-{4-[4-(2-Ethoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(2-ethoxy-phenyl)-piperazine to give the title compound (475 mg, 87%).MS: APCl: M+1:425.2 (Exact Mass: 424.25).

Example A21 Synthesis of7-{4-[4-(2-Chloro-3-ethoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate, 2-Chloro-3-ethoxy-nitro-benzene, was produced asfollows: A slurry of 2-chloro-3-nitrophenol (5 g, 28.8 mmol), potassiumcarbonate (4.0 g, 28.8 mmol), and iodoethane (4.8 mL, 60 mmol) inacetonitrile (100 mL) was heated under reflux for 6 h. After cooling,the salts were removed by filtration and the filtrate concentrated to asolid. The solid was triturated in diethyl ether (100 mL). The triturantwas concentrated to provide the first intermediate compound (6.5 g).Proton NMR indicated a spectrum consistent with that of the structure ofthe compound.

A second intermediate compound, 2-Chloro-3-ethoxy-aniline, was producedas follows: To a solution of 2-chloro-3-ethoxy-nitro-benzene (6.5 g,28.8 mmol), water (50 mL), and glacial acetic acid (16.5 mL) in methanol(200 mL) was added Fe dust (16.1 g, 28.8 mmol). The slurry was heatedunder reflux for 90 minutes, cooled, and filtered. The filtrate wasconcentrated in vacuo to a solid which was triturated in water (˜100 mL)to provide the acetate salt of the desired product. This salt, which wasonly sparingly soluble in water, was converted to the free base withNaHCO₃ and extracted into CHCl₃, dried over Na₂SO₄, and concentrated toprovide the second intermediate compound (5 g). MS: APCl: M+1:171.9(Exact Mass: 171.05).

A third intermediate compound, 1(2-Chloro-3-ethoxy-phenyl)-piperazine,was produced as follows: A mixture of 2-chloro-3-ethoxy-aniline (3.0 g,17.5 mmol) and bis(2-chloroethyl)amine hydrochloride (3.12 g, 17.5 mmol)was heated under reflux in chlorobenzene (20 mL) for 48 h. Diethyl ether(200 mL) was added to the cooled solution to provide a crunchy solidthat was collected by filtration. An aqueous solution of this materialwas treated with saturated NaHCO3, extracted into CHCl3, dried overNa2SO4, and concentrated to an oil which was purified by chromatography(MPLC, elution with 15% MeOH in CHCl3) to provide the third intermediatecompound (3.5 g, 14.6 mmol, 83%) as an oil. MS: APCl: M+1:241.1 (ExactMass: 240.10).

Finally, a solution of4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(0.4 g, 1.17 mmol) and 1(2-chloro-3-ethoxy-phenyl)-piperazine (0.445 g,1.85 mmol) in 1,2-dichloroethane (30 mL) was stirred for 15 min beforeNaBH(OAc)₃ (0.46 g, 2.17 mmol) was added as a powder. The reaction wasstirred at room temperature for 18 h and quenched with saturated NaHCO₃and H₂0. The mixture was extracted with CHCl₃. The organic layer waswashed with saturated NaHCO₃, H₂O and brine, dried over Na₂SO₄ andconcentrated to afford an oil. Purification by liquid chromatography (1%MeOH/CH₂Cl₂) gave the product as a white foam. Trituration of this foamin a minimal amount of diethyl ether provided the title compound aswhite crystals (300 mg, 0.655 mmol, 56%). mp 110-112° C. MS: APCl:M+1:459.2 (Exact Mass: 458.21).

Example A22 Synthesis of7-{4-[4-(2-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

1-(2-Chloro-3-methoxy-phenyl)-piperazine was prepared according to theprocedure for 1-(2-chloro-3-ethoxy-phenyl)-piperazine in Example A21.

The reductive amination procedure from Example A21 was followed usingthe 1-(2-chloro-3-methoxy-phenyl)-piperazine to give the title compound.MS: APCl: M+1:445.6 (Exact Mass: 444.19).

Example A23 Synthesis of7-{4-[4-(2-Chloro-3-isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

1-(2-Chloro-3-isopropoxy-phenyl)-piperazine was prepared according tothe procedure for 1-(2-chloro-3-ethoxy-phenyl)-piperazine in ExampleA21.

The reductive amination procedure from Example A21 was followed using1-(2-chloro-3-isopropoxy-phenyl)-piperazine to give the title compound.MS: APCl: M+1:473.2 (Exact Mass: 472.22).

Example A24 Synthesis of7-{4-[4-(3-Methoxy-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(3-methoxy-2-methyl-phenyl)-piperazine to give the title compound. MS:APCl: M+1:425.2 (Exact Mass: 424.25).

Example A25 Synthesis of7-{4-[4-(5-Chloro-2-isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

To a suspension of4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(0.241 g, 1.02 mmol, 1 eq) and1-(5-chloro-2-isopropoxy-phenyl)-piperazine (0.382 g, 1.13 mmol, 1.1 eq)in dichloroethane (5 mL) was added NaBH(OAc)₃ (0.583 g, 2.75 mmol, 2.67eq). The slurry was allowed to stir overnight at room temperature (18h). Analysis by HPLC showed reaction mostly complete. The mixture wasdiluted with EtOAc and quenched with saturated NaHCO₃. The organic phasewas then washed with brine, dried over Na₂SO₄, filtered and evaporatedin vacuo. Purification by silica gel chromatography (100% EtOAc)followed by formation of the HCl salt using 1N HCl in ether provided thetitle compound (0.219 g, 25%). MS: APCl: M+1:473.2 (Exact Mass: 472.22).

Example A26 Synthesis of7-{4-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The above reductive amination procedure in Example A25 using1-(2-isopropoxy-phenyl)-piperazine provided the title compound (0.152 g,32%). CHN found: C, 67.72;H, 7.81; N, 12.55. This calculates out forC₂₅H₃₄N₄O₃ plus 0.13H₂O (residual solvent).

Example A27 Synthesis of7-{4-[4-(2-lsobutoxy-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The above reductive amination procedure in Example A25 using1-(2-isobutoxy-phenyl)-piperazine provided the title compound (0.177 g,37%). CHN found: C, 63.22;H, 7.65; N, 11.19. This calculates out forC₂₆H₃₆N₄O₃×1.05 HCl.

Example A28 Synthesis of7-{4-[4-(2-Acetyl-3-chloro-phenyl)-pierazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound, 1-(2-Chloro-6-piperazin-1-yl-phenyl)-ethanone,was produced as follows: To a 250 mL flask was added piperazine (72 g,0.834 mol) and 1-(2-chloro-6-fluoro-phenyl)-ethanone (24 g, 0.139 mol)followed by heating to 120° C. for 2 hours. Excess piperazine was thendistilled from the flask under vacuum leaving a brown oil whichsolidified. This oil (10 g) was purified by chromatography on silica gel(dichloromethane/methanol 98:2) to give the intermediate compound (4.89g).

In a manner similar to that of other examples, above,1-(2-chloro-6-piperazin-1-yl-phenyl)-ethanone was coupled by reductiveamination to4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowed by typical workup and purification to give the title compound,mp 115° C. MS: APCl: M+1:457.2 (Exact Mass: 456.19).

Example A29 Synthesis of7-{4-[4-(3-Chloro-2-ethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound, 1-(3-Chloro-2-ethyl-phenyl)-piperazinehydrochloride, was produced as follows: To1-(2-chloro-6-piperazin-1-yl-phenyl)-ethanone (2.45 g, 10.3 mmol) wasadded trifluoroacetic acid (18 g) and triethylsilane (18 g) followed byheating to reflux for 5 hours. Upon cooling, the solution was evaporatedand the residue suspended in water. The pH was adjusted to 13 byaddition of 4N NaOH followed by extraction with diethyl ether. Theorganic layer was dried over magnesium sulfate and evaporated to give ayellow oil which was distilled and crystallized as the hydrochloridesalt from an ether solution by addition of ethereal HCl.

In a manner similar to that of other examples above,1-(3-chloro-2-ethyl-phenyl)-piperazine hydrochloride was coupled byreductive amination to4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowed by typical workup and purification to give the title compound.MS: APCl: M+1: 443.2 (Exact Mass: 442.21).

Example A30 Synthesis of7-{4-[4-(2-Acetyl-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,4-(2-Acetyl-3-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butylester, was produced as follows: To acetonitrile (100 mL) was addedboc-piperazine (28.63 g, 0.153 mol), 2,6-difluoroacetophenone (24 g,0.154 mol), potassium carbonate (53 g, 0.384 mol) and potassium fluoride(8.93 g, 0.154 mol) followed by heating to 100° C. for 24 hours.Concentration of the solution in vacuo gave a mixture of solids whichwere isolated by filtration. The first intermediate compound wasobtained by recrystallization from ethyl acetate, mp 88° C.

A second intermediate compound,1-(2-Fluoro-6-piperazin-1-yl-phenyl)-ethanone, was produced as follows:To dichloromethane (10 mL) was added4-(2-acetyl-3-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butylester giving a solution. Trifluoroacetic acid (2.12 g) was addedfollowed by stirring at 25° C. for 3 hours. The mixture was evaporatedand the residue taken up into diethyl ether and water. The pH was thenadjusted to 13 by addition of 4N NaOH and the ether phase was decanted.The ether phase was dried over magnesium sulfate, filtered andconcentrated in vacuo to give the title compound as a white solid (1.09g), mp 64° C.

In a manner similar to that of other examples above,1-(2-fluoro-6-piperazin-1-yl-phenyl)-ethanone was coupled by reductiveamination to4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowed by typical workup and purification to give the title compound.MS: APCl: M+1: 441.3 (Exact Mass: 440.22).

Example A31 Synthesis of7-{4-[4-(2-Ethyl-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound, 1-(2-Ethyl-3-fluoro-phenyl)-piperazinehydrochloride, was produced as follows: To4-(2-acetyl-3-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butylester (2.0 g, 6.2 mmol) was added trifluoroacetic acid (10.6 g) andtriethylsilane (7.2 g) followed by heating to reflux for 5 hours. Uponcooling, the solution was evaporated and the residue suspended in water.The pH was adjusted to 13 by addition of 4N NaOH followed by extractionwith diethyl ether. The organic layer was dried over magnesium sulfateand evaporated to give a yellow oil which was distilled and crystallizedas the hydrochloride salt from an ether solution by addition of etherealHCl giving the intermediate compound (0.907 g).

In a manner similar to that of other examples above,1-(2-ethyl-3-fluoro-phenyl)-piperazine hydrochloride was coupled byreductive amination to4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowed by typical workup and purification to give the title compound.MS: APCl: M+1: 427.2 (Exact Mass: 426.24).

Example A32 Synthesis of7-{4-[4-(3-Acetyl-2-chloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, 1-(3-Amino-2-chloro-phenyl)-ethanone, wasproduced as follows: To THF (400 mL) was added1-(2-chloro-3-nitro-phenyl)-ethanone (13.1 g, 065.6 mmol, EuropeanJournal of Medicinal Chemistry, 1989, 24, 479-84) followed by RaneyNickel (2.0 g) and pressurization to 25 psi with hydrogen gas over 24hours. The mixture was filtered and evaporated to an oil. The oil wasresuspended in water and diethyl ether, filtered and the organic phasedecanted. Addition of hexane gave a crystalline solid, which wasfiltered and dried in vacuo to give the first intermediate compound as asolid (9.3 g).

A second intermediate compound,4-(3-Acetyl-2-chloro-phenyl)-piperazine-1-carboxylic acid tert-butylester, was produced as follows: In a manner similar to the preparationof 1-(6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl)-piperazine,1-(3-amino-2-chloro-phenyl)-ethanone was converted to crude1-(2-chloro-3-piperazin-1-yl-phenyl)-ethanone (8.51 g, 35.6 mmol) towhich was added di-t-butyloxycarbonate (7.78 g, 35.6 mmol) as a solutionin dichloromethane (40 mL). After 2 hours the mixture was concentratedand purified by chromatography on silica gel eluting withdichloromethane and ethyl acetate to give the second intermediatecompound as an oil (4.96 g).

A third intermediate compound,1-(2-Chloro-3-piperazin-1-yl-phenyl)-ethanone trifluoroacetate, wasproduced as follows: To dichloromethane (10 mL) was added4-(3-acetyl-2-chloro-phenyl)-piperazine-1-carboxylic acid tert-butylester (1.01 g, 2.98 mmol) followed by trifluoroacetic acid (0.5 mL). Themixture was stirred at 25° C. for 2 hours, and the solvent removed byevaporation to give third intermediate compound as an oil.

In a manner similar to that of other examples above,1-(2-chloro-3-piperazin-1-yl-phenyl)-ethanone trifluoroacetate wascoupled by reductive amination to4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowed by typical workup and purification to give the title compound,mp 138-139° C. MS: APCl: M+1:457.2 (Exact Mass: 456.19).

Example A33 Synthesis of7-{4-[4-(3-Acetyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(3-piperazin-1-yl-phenyl)-ethanone to give the title compound. MS:APCl: M+1:423.2 (Exact Mass: 422.23).

Example A34 Synthesis of7-{4-[4-(2-Acetyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(2-piperazin-1-yl-phenyl)-ethanone to give the title compound. MS:APCl: M+1:423.3 (Exact Mass: 422.23).

Example A35 Synthesis of7-{4-[4-(2-Ethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(2-ethyl-phenyl)-piperazine to give the title compound. MS: APCl:M+1:409.2 (Exact Mass: 408.25).

Example A36 Synthesis of7-[4-(4-o-Tolyl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(2-methyl-phenyl)-piperazine to give the title compound. MS: APCl:M+1: 395.2 (Exact Mass: 394.24).

Example A37 Synthesis of7-{4-[4-(2-Trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(2-trifluoromethyl-phenyl)-piperazine to give the title compound. MS:APCl: M+1:449.2 (Exact Mass: 448.21).

Example A38 Synthesis of7-{4-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(3-trifluoromethyl-phenyl)-piperazine to give the title compound. MS:APCl: M+1:449.3 (Exact Mass: 448.21).

Example A39 Synthesis of7-[4-(4-Phenyl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-phenyl-piperazine to give the title compound. MS: APCl: M+1:381.1(Exact Mass: 380.22).

Example A40 Synthesis of7-{4-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(4-fluoro-phenyl)-piperazine to give the title compound. MS: APCl:M+1: 399.4 (Exact Mass: 398.21).

Example A41 Synthesis of7-{4-[4-(2,4-Difluoro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-(2,4-difluoro-phenyl)-piperazine to give the title compound. MS: APCl:M+1: 417.2 (Exact Mass: 416.20).

Example A42 Synthesis of7-(4-{4-[2-(1,1-Difluoro-ethyl)-pheny]-piperazin-1-yl}-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, 1-Bromo-2-(1,1-difluoro-ethyl)-benzene,was produced as follows: A solution of 1-(2-bromo-phenyl)-ethanone (3.98g, 20 mmol) in DAST (5.3 mL, 40 mmol) was heated at 55° C. for 48 h,cooled to RT, diluted with CCl₄ (20 mL) and poured into ice (100 g). Themixture was extracted with CCl₄ (2×40 mL). The combined organic phaseswere dried, concentrated, and purified by chromatography on silica gelto give the first intermediate compound (2.2 g, 50%). ¹H NMR (400 MHz,CDCl₃): δ 7.60 (m, 2H), 7.45 (t, 1H), 7.20 (m, 1H), 2.05 (t, 3H).

A second intermediate compound,1-[2-(1,1-Difluoro-ethyl)-phenyl]-piperazine, was produced as follows:To a mixture of 1-bromo-2-(1,1-difluoro-ethyl)-benzene (1.3 g, 5.91mmol), piperazine (0.64 g, 7.39 mmol), Pd₂(dba)₃ (1.30 g, 1.42 moml),BINAP (0.82 g, 2.63 mmol), NaOtBu (0.80 g, 8.30 mmol) in toluene (40 mL)was bubbled N₂ gas for 10 min. The mixture was then heated at 110° C.for 2 h, cooled to RT, diluted with EtOAc (300 mL), filtered through apad of celite and concentrated. The residue was treated with 1 N HCl topH=2 and washed with ether (2×50 mL). The aqueous phase was basifiedwith K₂CO₃ to pH=11 and extracted with CH₂Cl₂ (3×50 mL). The combinedorganic phases were dried and concentrated to give the secondintermediate compound (0.80 g, 60%). ¹H NMR (400 MHz, CDCl₃): δ 7.60 (m,1H), 7.40 (m, 1H), 7.38 (m, 1H), 7.20 (m, 1H), 3.00 (m, 4H), 2.90 (m,4H), 2.10 (t, 3H).

The reductive amination procedure from Example A1 was followed using1-[2-(1,1-difluoro-ethyl)-phenyl]-piperazine to give the title compound(0.48 g, 91%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.40 (s, 1H), 10.20 (s,1H), 7.50 (m, 4H), 7.35 (m, 1H), 6.40 (d, 1H), 4.20 (s, 2H), 3.60 (m,2H), 3.30-3.00 (m, 8H), 2.80 (m, 2H), 2.50 (m, 2H), 2.10 (t, 3H),1.90-1.70 (m, 4H).

Example A43 Synthesis of7-[4-(4-Pyridin-2-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1-pyridin-2-yl-piperazine to give the title compound. MS: APCl:M+1:382.1 (Exact Mass: 381.22).

Example A44 Synthesis of7-{4-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthvridin-2-one

To a suspension of 1-(6-methyl-pyridin-2-yl)-piperazine bishydrochloride(0.77 g, 3.08 mmol) in dichloroethane (10 mL) was added Et₃N (1.0 mL,7.17 mmol) and the mixture was stirred for 30 min.4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(0.85 g, 3.63 mmol) was added as a solution in dichloroethane (3 mL) andthe mixture was stirred at room temperature for 15 min. NaBH(OAc)₃ (1.1g, 5.2 mmol) was added as a solid and the mixture was stirred at roomtemperature for 3 h. The reaction was poured into EtOAc and washed withsaturated NaHCO₃ and brine, dried over MgSO₄ and concentrated. Theresidue was partitioned between EtOAc and pH 4.5 aqueous citric acid.The product went into the aqueous layer selectively over the impurities.The aqueous layer was neutralized with solid NaHCO₃ to pH 8 andextracted with EtOAc. The organic layer was washed with brine, driedover MgSO₄ and concentrated to give the title compound as a sticky foam(0.77 g). The foam was dissolved in Et₂O and treated with anhydrous HClgas to give a white precipitate. The mixture was filtered, washed withEt₂O and hexanes, and dried to give a white solid (616 mg). MS: APCl:M+1:396.1 (Exact Mass: 395.23).

Example A45 Synthesis of7-{4-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

To a solution of 1-(6-ethyl-pyridin-2-yl)-piperazine (0.41 g, 2.13 mmol)in dichloroethane (15 mL) was added Et₃N (0.22 g, 2.13 mmol) and themixture was stirred for 5 min.4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(0.50 g, 2.13 mmol) was added as a solution in dichloroethane (3 mL) andthe mixture was stirred at room temperature for 15 min. NaBH(OAc)₃ (0.63g, 3.00 mmol) was added as a solid and the reaction was stirred at roomtemperature for 2 h. The reaction was quenched with saturated NaHCO₃ andextracted with EtOAc. The organic layer was washed with brine, driedover MgSO₄ and concentrated. Purification by liquid chromatography(Biotage 40M, gradient elution 100% CH₂Cl₂ to 99% CH₂Cl₂/MeOH) affordedthe title compound as a sticky white foam (413 mg, 1.01 mmol, 47%). Thefoam was dissolved in Et₂O and treated with anhydrous HCl gas to give awhite precipitate. The mixture was filtered and dried to give a whitepowder (287 mg). MS: APCl: M+1:410.3 (Exact Mass: 409.25).

Example A46 Synthesis of7-{4-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A mixture of4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(0.47 g, 2.0 mmol) and 1-(6-cyclopropyl-pyridin-2-yl)-piperazine (0.41g, 2.0 mmol) in dichloroethane (12 mL) was stirred for 20 min andNaBH(OAc)₃ (0.55 g, 2.6 mmol) was added. The reaction was stirred atroom temperature for 2.5 h. The reaction was quenched with saturatedNaHCO₃ and extracted with Et₂O. The organic layer was washed with brine,dried over MgSO₄ and concentrated. Purification by liquid chromatography(Biotage 12M, eluted with CHCl₃) gave the title compound as an oil. Theoil was dissolved in Et₂O and treated with anhydrous HCl gas to give aprecipitate. The mixture was filtered, washed with Et₂O and hexanes anddried to give a white solid (121 mg). MS: APCl: M+1:422.3 (Exact Mass:421.25).

Example A47 Synthesis of7-{4-[4-(4-Methyl-pyrimidin-2-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

In a manner similar to that of other examples above,4-methyl-2-piperazin-1-yl-pyrimidine hydrochloride (U.S. Pat. No.6,303,603) was coupled by reductive amination to4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowed by typical workup and purification to give the title compound.MS: APCl: M+1:397.2 (Exact Mass: 396.23).

Example A48 Synthesis of7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The procedure in Example A1 was followed using1-naphthalen-1-yl-piperazine hydrochloride. Purification by liquidchromatography (4% MeOH/CH₂Cl₂) gave the title compound as a white foam(595 mg, 1.38 mmol). The foam was dissolved in Et₂O and 1 N HCl in Et₂O(1.4 mL) was added. The resulting white precipitate was collected byfiltration, washed with Et₂O and dried to give a white solid (600 mg).¹H NMR (400 MHz, d₆-dmso) δ 10.69 (bs, 1H), 10.26 (s, 1H), 8.10 (m, 1H),7.88 (m, 1H), 7.63 (d, 1H), 7.52-7.41 (m, 4H), 7.14 (d,1H), 6.34 (d,1H), 4.20 (t, 2H), 3.59 (m, 2H), 3.39 (m, 4H), 3.22 (m, 4H), 2.75 (t,2H), 2.44 (t, 2H), 1.87 (bm, 2H), 1.75 (m, 2H). MS: APCl: M+1:431.2(Exact Mass: 430.24).

Example A49 Synthesis of7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The procedure in Example A1 was followed using1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine. Purification byliquid chromatography (0-5% MeOH/CH₂Cl₂) gave the title compound as awhite foam (668 mg, 1.53 mmol). The foam was dissolved in CH₃CN and asolid crashed out, which was collected by filtration, washed with Et₂Oand dried to give a white solid (657 mg, 1.51 mmol, 52%). MS: APCl:M+1:435.2 (Exact Mass: 434.27).

Example A50 Synthesis of7-{4-[4-(3-Fluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example A1 was followed using1(3-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to give thetitle compound (0.461 g; 72 %). MS: APCl: M+1:453.3 (Exact mass:452.26).

Example A51 Synthesis of7-{4-[4-(8-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,8-Hydroxy-3,4-dihydro-2H-naphthalen-1-one, was produced as follows: Asolution of naphthalene-1,8-diol (1.00 g, 6.24 mmol, J. Org. Chem. 2002,67, 5190) in ethanol (100 mL) was treated with 10% Pd/C (wet, 0.342 g),then hydrogenated at 50 psi H₂ for 3 hours. The mixture was filteredthrough a Celite pad and the pad was rinsed with ethanol. The filtratewas concentrated under vacuum to give a brown oil. The oil was purifiedby column chromatography (hexanes/ethyl acetate, 7:1) to afford thefirst intermediate compound (0.760 g, 78%) as a yellow liquid. ¹H NMR(400 MHz, DMSO-d₆) δ 12.44 (s, 1H), 7.46 (t, 1H), 6.80 (d, 1H), 6.77 (d,1H), 2.90 (t, 2H), 2.69 (t, 2H), 2.05-1.98 (m, 2H).

A second intermediate compound, trifluoro-methanesulfonic acid8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl ester, was produced as follows:An ice-cold brown solution of 8-hydroxy-3,4-dihydro-2H-naphthalen-1-one(0.76 g, 4.68 mmol) in dichloromethane (25 mL) was treated with lithiumchloride (0.20 g, 4.72 mmol), followed by triethylamine (0.65 mL, 4.66mmol). Trifluoromethanesulfonic anhydride (0.8 mL, 4.76 mmol) was addeddropwise to the mixture. After the exothermic reaction subsided, theresulting mixture was stirred at 0° C. for 1 hour, then quenched withwater and extracted with dichloromethane. The extracts were dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum to give a brownoil. The oil was purified by column chromatography (hexanes/ethylacetate, 4:1) to afford the second intermediate compound (1.164 g, 84%)as a yellow liquid. ¹H NMR (400 MHz, CDC1₃) 67 7.52 (t, 1H), 7.33 (d,1H), 7.13 (d, 1H), 3.04 (t, 2H), 2.72 (t, 2H), 2.20-2.10 (m, 2H).

A third intermediate compound,4-(8-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1 Carboxylicacid tert-butyl ester, was produced as follows: Tetrahydrofuran (20 mL)was degassed with nitrogen for 15 minutes, then treated with2-(di-tert-butylphosphino)biphenyl (0.304 g, 1.02 mmol) and degassed foranother 5 minutes. To this mixture was added trifluoro-methanesulfonicacid 8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl ester (3.00 g, 10.20mmol), Boc-piperazine (2.279 g, 12.20 mmol), and potassium phosphate(3.03 g, 14.27 mmol) followed by palladium acetate (0.228 g, 1.02 mmol)and the resulting mixture was degassed with nitrogen for 5 minutes. Thebrown suspension was heated at 80° C. for 3 days, then cooled to roomtemperature and diluted with ethyl acetate. The suspension was filteredthrough a Celite pad and the pad was rinsed with ethyl acetate. Thefiltrate was concentrated in vacuo to give a brown oil. The oil waspurified by column chromatography (hexanes/ethyl acetate, 7:1 to 3:1gradient) to afford the third intermediate compound (1.237 g, 37%) as abrown oil. ¹H NMR (400 MHz, CDCl₃) δ 7.34 (t, 1H), 6.86 (t, 2H),3.70-3.62 (m, 4H), 3.06-2.96 (m, 4H), 2.94 (t, 2H), 2.62 (t, 2H),2.10-2.00 (m, 2H), 1.48 (s, 9H).

A fourth intermediate compound,8-Piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one, was produced asfollows: A brown solution of4-(8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylicacid tert-butyl ester (1.089 g, 3.30 mmol) in dichloromethane (10 mL)was treated with trifluoroacetic acid (5 mL, 64.9 mmol). The resultingmixture was stirred at room temperature for 1.5 hours. The dark brownsolution was concentrated under vacuum to afford the fourth intermediatecompound (1.03 g, quantitative) as a brown oil. ¹H NMR (400 MHz,DMSO-d₆) 67 8.69 (br s, 2H), 7.43 (t, 1H), 6.96 (d, 2H), 3.31-3.23 (m,4H), 3.16-3.11 (m, 4H), 2.91 (t, 2H), 2.54 (t, 2H), 1.99-1.91 (m, 2H).

The reductive amination procedure from Example A1 was followed using8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one to give the titlecompound (0.411 g, 61%). ¹H NMR (400 MHz, CDCl₃) δ 7.53 (br s, 1H), 7.36(d, 1H), 7.32 (d, 1H), 6.88 (d, 1H), 6.81 (d, 1H), 6.35 (d, 1H), 4.22(d, 2H), 3.14-3.05 (m, 4H), 2.92 (d, 2H), 2.85 (d, 2H), 2.75-2.67 (m,4H), 2.67-2.59 (m, 4H), 2.49 (t, 2H), 2.08-2.00 (m, 2H), 1.84-1.75 (m,2H), 1.75-1.66 (m, 2H). MS ES: 449.26 (M+H)⁺ (Exact mass: 448.25).

Example A52 Synthesis of7-{4-[4-(7,7-Dimethyl-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,4-(7,7-Dimethyl-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylicacid tert-butyl ester, was produced as follows: To a stirred solution ofcompound4-(8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylicacid tert-butyl ester (1.25 g, 4.1 mmol) in anhydrous THF (20 mL) wasadded Mel (2.33 g, 16.4 mmol, 4.0 equiv). The reaction mixture wascooled to 0° C. and potassium tert-butoxide (1.4 g, 12.3 mmol, 3.0equiv) was added. The reaction mixture was warmed to room temperatureand stirred for 30 min. TLC indicated that the reaction was incomplete.Excess Mel (1.0 mL) was added and the stirring was continued at roomtemperature for an additional hour. The reaction mixture was quenchedwith water and extracted with ethyl acetate. The extracts were driedover Na₂SO₄ and concentrated to afford the first intermediate compound(1.20 g, 88%) as dark yellow thick oil which was carried to the nextstep without further purification. ¹HNMR: δ (CDCl₃, 400 MHz) 7.30 (t,1H), 6.90 (m, 2H), 3.70 (m, 4H), 3.00 (br s, 4H), 3.95 (t, 2H), 1.90 (t,2H), 1.50 (s, 9H), 1.20 (s, 6H); ESMS: 359.23 (Exact mass: 358.23).

A second intermediate compound,2,2-Dimethyl-8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1one, wasproduced as follows: An ice cold solution of4-(7,7-dimethyl-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.60 g, 1.8 mmol) in dichloromethane(10.0 mL)was treated with TFA (5.0 mL) and stirred for 2 h at roomtemperature. The solvents were removed under reduced pressure andpurified by column chromatography eluting with 5% methanol indichloromethane to afford the second intermediate compound (0.50 g, 77%)as yellow solid. ¹HNMR: δ (CDCl₃, 400 MHz) 9.80 (br s, 2H), 7.30 (t,1H), 6.90 (m, 2H), 3.50 (br s, 4H), 3.30 (br s, 4H), 3.00 (t, 2H), 1.90(t, 3H), 1.20 (s, 6H); ESMS: 259.14 (Exact mass: 258.17).

The reductive amination procedure from Example A1 was followed using2,2-dimethyl-8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one to givethe title compound (0.20 g, 60 %). ¹H-NMR: δ (CDCl₃, 400 MHz) 7.80 (brs, 1H), 7.40-7.20 (m, 2H), 6.90 (d, 1H), 6.85 (d, 1H), 6.40 (d, 2H),4.30 (m, 2H), 3.10 (br s, 4H), 3.00-2.80 (m, 4H), 2.80-2.60 (m, 6H),2.50 (t, 2H), 1.90-1.60 (m, 6H), 1.15-1.05 (m, 6H); ESMS: 477.25 (Exactmass: 476.28).

Example A53 Synthesis of7-{4-[4-(7,7-Dimethyl-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound,1-(7,7-Dimethyl-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine, wasproduced as follows:2,2-Dimethyl-8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one (0.60 g,1.8 mmol) was taken up in BF₃-OEt₂ (6.0 mL) and triethyl silane (1.8 mL,10.8 mmol, 6.0 equiv) was added. The reaction mixture was heated in asealed tube at 90° C. for 6 h. The sealed tube was cooled and excessether was added to the reaction mixture. A white precipitate was formedwhich was collected by filtration. The intermediate compound product(0.40 g, quantitative) was used in the next step without purification.¹H-NMR: δ (CDCl₃, 400 MHz) 7.60 (d, 1H), 7.20 (m, 2H), 4.00 (m, 2H),3.80 (m, 2H), 3.45 (m, 2H), 3.10 (m, 2H), 2.90 (t, 2H), 2.65 (s, 2H),1.60 (t, 2H). ESMS: 245.17 (Exact mass: 244.19).

The reductive amination procedure from Example A1 was followed using1-(7,7-dimethyl-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to givethe title compound. ¹H NMR: δ (CDCl₃, 400 MHz) 7.80 (br s, 1H), 7.40 (d,1H), 7.10 (t, 1H), 6.90 (m, 2H), 6.40 (d, 1H), 4.15 (t, 2H), 2.95-2.45(m, 16H), 1.80-1.70 (m, 4H), 1.50 (t, 2H), 1.25 (t, 2H), 1.00 (s, 6H).ESMS: 463.28 (Exact mass: 462.30).

Example A54 Synthesis of7-{4-[4-(7,7-Difluoro-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,4-(7,7-Difluoro-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylicacid tert-butyl ester, was produced as follows: 1M LiHMDS in THF (38.5mL, 38.5 mmol) was cooled to −78° C. and4-(8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylicacid tert-butyl ester (3.64 g, 11 mmol) in THF (8 mL) was addeddropwise. The reaction mixture was stirred at 0° C. for 2.5 h andre-cooled to −78° C. N-fluorobenzenesulfonimide (12.14 g, 38.5 mmol) inTHF (25 mL) was added dropwise and the reaction was stirred overnight atroom temperature. Saturated NH₄Cl solution was added and the mixture wasextracted with Et₂O. Column chromatography of the orange oily material,eluting with EtOAc:Hex (2:8) and then changing to (2.5:7.5) gave thefirst intermediate compound (0.42 g) as a thick orange oil, along with amixture of the title compound with monofluorinated compound (1.69 g). ¹HNMR (400 MHz, CDCl₃) δ 7.42 (t, 1H), 6.91 (d, 1H), 6.83 (d, 1H), 3.72(m, 4H), 3.16 (t, 2H), 3.11-2.96 (br s, 4H), 2.56-2.42 (m, 2H) 1.43 (s,9H).

A second intermediate compound,2,2-Difluoro-8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1one, wasproduced as follows: To a solution of4-(7,7-difluoro-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1carboxylicacid tert-butyl ester (0.42, 1.14 mmol) in methanol (10 mL) was addeddropwise acetyl chloride (0.8 mL, 11.46 mmol). The reaction mixture wasstirred overnight at room temperature. The solvent was evaporated undervacuum, and trituration with diethyl ether yielded the secondintermediate compound (0.31 g, quant) as yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 7.58 (t, 1H), 7.06 (d, 1H), 7.03 (d, 1H), 3.34 (m, 6H), 3.21(m, 4H), 3.11 (m, 2H).

The reductive amination procedure from Example A1 was followed using2,2-difluoro-8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one to givethe title compound. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.24 (s, 1H), 7.61 (t,1H), 7.56 (d, 1H), 7.08 (d, 1H), 7.06 (d, 1H), 6.38 (d, 1H), 4.22 (t,2H), 3.62 (m, 2H), 3.41-3.03 (m, 11), 2.78 (t, 2H), 2.62-2.42 (m, 4H)1.98-1.74 (m, 4H).

Example A55 Synthesis of7-{4-[4-(7,7-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,4-(7,7-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylicacid tert-butyl ester, was produced as follows: An ice-cold solution of4-(7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylicacid tert-butyl ester (0.720 g, 2.20 mmol) in dichloromethane (10 mL)was treated with bis(2-methoxyethyl)aminosulfur trifluoride (1 mL, 5.40mmol). The dark brown solution was warmed to room temperature andstirred overnight. The mixture was carefully diluted with water andextracted with dichloromethane. The extracts were dried over anhydrousNa₂SO₄, filtered and concentrated under vacuum to give a brown oil. Theoil was purified by column chromatography (hexanes/ethyl acetate, 10:1)to afford the first intermediate compound (0.172 g, 22%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 7.19 (t, 1H), 6.98-6.92 (m, 2H),3.66-3.40 (m, 4H), 3.24 (t, 2H), 3.02 (t, 2H), 2.88-2.74 (m, 4H),2.28-2.14 (m, 2H), 1.49 (s, 9H).

A second intermediate compound,1-(7,7-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine, wasproduced as follows: An ice-cold solution of methanol (3 mL) was treatedwith acetyl chloride (0.6 mL), then stirred at 0° C. for 15 minutes.4-(7,7-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine-1-carboxylicacid tert-butyl ester (0.172 g, 0.49 mmol) was added giving a clearyellow solution, which slowly clouded over time. After stirring at roomtemperature for 1.5 hours, the suspension was diluted with diethyl etherand the second intermediate compound (0.141 g, quantitative) wascollected by vacuum filtration as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.04 (br s, 2H), 7.21 (t, 1H), 7.02-6.97 (m, 2H), 3.34-3.20(m, 6H), 3.06-2.92 (m, 6H), 2.30-2.14 (m, 2H).

The reductive amination procedure from Example A1 was followed using1-(7,7-difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to givethe title compound (0.271 g, 92%). ¹H NMR (400 MHz, CDCl₃) δ 7.57(br s,1H), 7.36 (d, 1H), 7.17 (t, 1H), 7.00 (d, 1H), 6.92 (d, 1H), 6.36 (d,1H), 4.23 (t, 2H), 3.22 (t, 2H), 3.01 (t, 2H), 2.95-2.83 (m, 6H),2.70-2.58 (m, 6H), 2.49 (t, 2H), 2.26-2.13 (m, 2H), 1.86-1.75 (m, 2H),1.74-1.64 (m, 2H). ES MS: 471.26 (M+1)⁺ (Exact mass: 470.25).

Example A56 Synthesis of7-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,1-(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazine, was produced asfollows: Ammonia (30 mL) was collected in a 3-neck 125 mL round bottomflask at −78° C. To this was added sequentially isopropanol (7 mL),1-(7-methoxy-naphthalen-1-yl)-piperazine (3.0 g, 8.43 mmol), andtetrahydrofuran (7 mL). To the dark brown solution was added metallicsodium (795 mg, 35 mmol) portionwise over 10 minutes. The blue solutionwas stirred at −78° C. for 1 hour, then warmed to room temperature over2 hours. Water (150 mL) was added and the mixture was stirred 10 minutesand the grey precipitate was filtered off and rinsed with water (2×20mL) to yield the first intermediate compound (1.47 g, 71%) as a greysolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.22 (t,1H), 6.80-6.65 (m, 2H), 4.63(t, 1H), 3.55 (s, 3H), 3.80-3.70 (m, 2H), 3.65-3.55 (m, 3H), 2.86 (t,4H), 2.70 (t, 4H).

A second intermediate compound,7-{4-[4-(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows:1(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazine (329 mg, 1.35 mmol)and 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(300 mg, 1.28 mmol) were dissolved in dichloroethane (10 mL).Triethylamine (329 mg, 3.85 mmol) was added and the mixture was stirredfor 10 minutes. Sodium triacetoxyborohydride (285 mg, 1.35 mmol) wasadded and the mixture was stirred for 1 hour. The mixture was quenchedwith water (20 mL) and extracted with dichloromethane (20 mL). Theorganic layer was washed with brine (20 mL), dried over anhydrous sodiumsulfate, filtered and evaporated. The crude solid was purified by columnchromatography (5:95 methanoVethyl acetate) to yield the secondintermediate compound (330 mg, 56%) as a white foam. ¹H NMR (400 MHz,CDCl₃) δ 7.55 (s, 1H), 7.36 (d, 1H), 7.17 (t, 1H), 7.00-6.85 (m, 2H),6.38 (d, 1H), 4.80 (t, 1H), 4.20 (t, 2H), 3H), 3.50-3.45 (m, 2H),3.44-3.38 (m, 2H), 3.00-2.90 (m, 4H), 2.88 (t, 2H), 2.70-2.50 (m, 6H),2.50-2.40 (m, 2H), 1.85-1.55 (m, 4H).7-{4-[4-(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one(325 mg, 0.704 mmol) was dissolved in ethanol (5 mL) and 10% HCl (1 mL).The mixture was stirred at room temperature for 2 hours then quenchedwith saturated sodium bicarbonate (10 mL) and extracted with ethylacetate (20 mL). The organic layer was washed with brine (20 mL), driedover anhydrous sodium sulfate, filtered and evaporated. The crude solidwas purified by column chromatography (2:98 methanol/ethyl acetate) toyield the title compound (180 mg, 57%) as a white foam. ¹H NMR (400 MHz,CDCl₃) δ 7.60 (s, 1H), 7.38 (d, 1H), 7.20 (t, 1H), 7.02-6.96 (m, 2H),6.36 (d, 1H), 4.20 (t, 2H), 3.60 (s, 2H), 2.06 (t, 2H), 3.00-2.80 (m,6H), 2.80-2.40 (m, 10H), 1.80-1.60 (4H); MS ES+ 449.06 (M+H)⁺ (Exactmass: 448.25).

Example A57 Synthesis of7-{4-[4-(7-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

To a solution of7-{4-[4-(7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.24 9, 0.54 mmol) in methanol (5 mL) was added portionwise NaBH₄(0.081 g, 2.14 mmol). The reaction mixture was stirred at roomtemperature for 30 min and quenched with saturated NH₄Cl solution andthe compound was extracted with CH₂Cl₂ (2×20 mL). The organic layer waswashed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andevaporated. The crude product was purified by column chromatography (10%methanol in ethyl acetate) to afford compound the title compound (0.16g, 67%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.54 (s, 1H), 7.36(d, 1H), 7.12 (t, 1H), 6.93-6.85 (m, 2H), 6.35 (d, 1H), 4.23 (t, 2H),4.14-4.09 (m, 1H), 3.20-3.19 (m, 1H), 3.02-2.83 (m, 8H), 2.66-2.47 (m1OH), 1.83-1.67 (m, 6H). ES MS: 451.27 (M+H)⁺ (Exact mass: 450.26).

Example A58 Synthesis of7-{4-[4-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, 5-Amino-3,4-dihydro-2H-naphthalen-1-one,was produced as follows: 5-Nitro-3,4-dihydro-2H-naphthalen-1-one (Chem.Pharm. Bull. 1988, 36, 481) was dissolved in THF (400 mL) and RaNi (3 g)was added, followed by pressurization of the reaction vessel to 100 psiwith hydrogen gas. Upon completion, the solution was evaporated in vacuogiving a solid, which was crystallized from dichloromethane/hexane toyield the first intermediate compound (16.54 g). mp 118-120 ° C.

A second intermediate compound,3-[2-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-1-ylamino)-ethyl]-oxazolidin-2-one,was produced as follows: According to a method described in theliterature (Tetrahedron Lett. 1994, 35, 7331), to acetonitrile (300 mL)was added 5-amino-3,4-dihydro-2H-naphthalen-1-one (10 g), cesiumcarbonate (30.0 g) and toluene-4-sulfonic acid2-(2-oxo-oxazolidin-3-yl)-ethyl ester (34 g) under nitrogen followed byheating at 100° C. for 48 hours. The solvent was removed in vacuo, andthe residue was taken up in dichloromethane and diluted with brine. Thedichloromethane phase was dried over sodium sulfate and charcoal. Thefiltrate was evaporated to an oil (17.7g), which crystallized uponstanding. Repeated trituration with diethyl ether selectively removedexcess reagents and impurities. The remaining solid was dissolved indichloromethane and chromatographed on silica gel (dichloromethane witha gradient to 4% methanol). The second intermediate compoundcrystallized from diethyl ether/dichloromethane (8.8 g).

A third intermediate compound,5-Piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one, was produced asfollows:3-[2-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-1-ylamino)-ethyl]-oxazolidin-2-one(8.6 g) was dissolved in 200 mL dichloromethane. The solution wassparged with anhydrous HBr gas, precipitating a yellow-green oil. Thesolution was evaporated to a yellow brittle foam. The foam was heated byoil bath to 175° C. for 1.5 hours. The foam melted and re-expanded as abrittle foam with off-gassing. This foam again melted and solidified.The residue was taken up into 200 mL of a 50:50 water:dichloromethanemixture. The solution was filtered, agitated and the dichloromethanephase was decanted. The pH of the aqueous phase was adjusted to 14 with4N NaOH and the mixture was extracted with dichloromethane. Thedichloromethane solution was dried over sodium sulfate and filtered thrua short plug of silica gel. The filtrate was evaporated to an oil (7.7g). This was suspended in diethyl ether, filtered to remove minorinsoluble material and sparged with anhydrous HCl gas to yield a solidprecipitate. The suspension was filtered, washed with ether and dried invacuo to give the third intermediate compound as the hydrochloride salt(5.55 g, 66%).

In a manner similar to that of other examples above,5-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one was coupled byreductive amination to4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowed by typical workup and purification to give the title compound,mp 169-170° C. MS: APCl: M+1:449.2 (Exact Mass: 448.25).

Example A59 Synthesis of7-{4-[4-(5,5-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,5-Bromo-1,1-difluoro-1,2,3,4-tetrahydro-naphthalene, was produced asfollows: A solution of 5-bromo-3,4-dihydro-2H-naphthalen-1-one (4.02 g,17.86 mmol) and bis-(2-methoxyethyl)aminosulfur trifluoride (6.5 mL,35.25 mmol) in a sealed plastic bottle was heated at 65° C. overnight.The brown solution was diluted with dichloromethane and washed withsaturated sodium bicarbonate solution. The organic extract was driedover anhydrous Na₂SO₄, filtered and concentrated under vacuum to a brownoil. The oil was purified by column chromatography (hexane) to affordthe first intermediate compound (1.749 g, 40%) as a yellow liquid. ¹HNMR (400 MHz, CDCl₃) δ 7.78 (d, 1H), 7.68-7.60 (m, 1H), 7.18 (t, 1H),2.85-2.79 (m, 2H), 2.31-2.19 (m, 2H), 2.06-1.98 (m, 2H).

A second intermediate compound,1-(5,5-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine, wasproduced as follows: A yellow solution of5-bromo-1,1-difluoro-1,2,3,4-tetrahydro-naphthalene (1.024 g, 4.14 mmol)in toluene (20 mL) was degassed with nitrogen for 30 minutes. Thesolution was treated with 2-(dicyclohexylphosphino)biphenyl (0.145 g,0.41 mmol) followed by piperazine (0.393 g, 4.56 mmol), sodiumtert-butoxide (0.600 g, 6.22 mmol) and palladium acetate (0.093g, 0.41mmol). The resulting brown solution was degassed with nitrogen for 10minutes, then heated at 110° C. for 1.5 hours. The mixture was cooled toroom temperature, then filtered through a Celite pad. The pad was rinsedwith dichloromethane and the filtrate was concentrated in vacuo to abrown liquid. The liquid was diluted with 3N HCl to pH 1 and thenextracted with dichloromethane. The organic layer was discarded and theaqueous layer was basified with 2N KOH solution to pH 12. The aqueouslayer was extracted with dichloromethane and the extracts were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford thesecond intermediate compound (0.310 g, 30%) as a brown oil. ¹H NMR (400MHz, CDCl₃) δ 7.43 (d, 1H), 7.30 (t, 1H), 7.11 (d, 1H), 3.06-2.97 (m,4H), 2.97-2.88 (m, 6H), 2.36-2.22 (m, 2H), 2.00-1.90 (m, 2H).

The reductive amination procedure from Example A1 was followed using1-(5,5-difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to givethe title compound (0.310 g, 60 %). ¹H NMR (400 MHz, CDCl₃) δ 7.58 (brs, 1H), 7.44 (d, 1H), 7.36 (d, 1H), 7.30 (t, 1H), 7.12 (d, 1H), 6.36 (d,1H), 4.20 (t, 2H), 2.92 (t, 4H), 2.86 (t, 2H), 2.82-2.76 (m, 2H),2.70-2.52 (m, 6H), 2.48 (t, 2H), 2.34-2.22 (m, 2H), 2.00-1.90 (m, 2H),1.84-1.76 (m, 2H), 1.74-1.65 (m, 2H). ES MS: 471.12 (M+H)⁺ (Exact mass:470.25).

Example A60 Synthesis of7-[4-(4-lndan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The procedure in Example A1 was followed using 1-indan-4-yl -piperazine.Purification by liquid chromatography (0-5% MeOH/CH₂Cl₂) gave the titlecompound as a white foam (545 mg, 1.29 mmol, 48%). The foam wasdissolved in Et₂O and 1 N HCl in Et₂O (1.3 mL) was added. The resultingwhite precipitate was collected by filtration, washed with Et₂O anddried to give a white solid (563 mg). MS: APCl: M+1:421.5 (Exact Mass:420.25).

Example A61 Synthesis of7-{4-[4-(2-Oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,4′-Bromo-1′,3′-dihydro-spiro[[1,3]dioxolane-2,2′-indene], was producedas follows: To a stirred solution of 4-bromo-indan-2-one (2.20 g, 10.40mmol) in benzene (60 mL) was added ethylene glycol and para-toluenesulfonic acid monohydrate (200 mg). The resulting mixture was heated at110° C. for 40 h using Dean-Stark apparatus. The solvent was removed invacuo, ethyl acetate was added and the solution was washed withsaturated sodium bicarbonate solution, water and brine. It was dried(Na₂SO₄) and the solvent was removed in vacuo to give the title compound(2.40 g, 90%) as a liquid. ¹H NMR (400 MHz, CDCl₃): 7.22 (d, 1H), 7.15(d, 1H), 6.95 (m, 1H) 3.95 (s, 4H), 3.20 (s, 2H), 3.15 (s, 2H).

A second intermediate compound,4-(1′,3′-Dihydro-spiro[[1,3]dioxolane-2,2′-inden]-4′-yl)-piperazine-1carboxylicacid tert-butyl ester, was produced as follows: To a stirred solution of4′-bromo-1′, 3′-dihydro-spiro[[1,3]dioxolane-2,2′-indene] (2.12 g, 8.35mmol) in toluene (40 mL) at room temperature, was added 1-boc-piperazine(1.86 g, 10.0 mmol), tris-(dibenzylideneacetone)di-palladium(0)(Pd₂(dba)₃, 1.91 g, 2.08 mmol),tert-2,2′-bis(diphenyl)phosphino-1,1′-binaphthyl (BINAP, 2.34 g, 3.76mmol) and cesium carbonate (4.08 g, 12.52 mmol). The resulting mixturewas degassed, filled with N₂, degassed and heated at 100° C. overnight.The mixture was diluted with ethyl acetate and filtered through a pad ofcelite. The filtrate was concentrated and the residue was purified bychromatography on silica (4:1 hexanes-ethyl acetate) to give the secondintermediate compound (1.60 g, 40 %) as an oil. ¹H NMR (400 MHz, CDCl₃):δ: 7.18 (m, 1H), 6.90 (d, 1H), 6.75 (d, 1H), 4.05 (s, 4H), 3.58 (m, 4H),3.20 (s, 2H), 3.10 (s, 2H), 2.95 (m, 4H), 1.50 (s, 9H).

A third intermediate compound, 4-Piperazin-1-yl-indan-2-one, wasproduced as follows: Trifluoroacetic acid-water (9:1, 50 mL) was addedto4-(1′,3′-dihydro-spiro[[1,3]dioxolane-2,2′-inden]-4′-yl)-piperazine-1-carboxylicacid tert-butyl ester (1.65 g, 4.58 mmol) cooled to 0° C. The resultingmixture was stirred at 0° C. for 3 h and the solvent was removed invacuo. Ether was added to the residue and the solid formed was filteredto give the third intermediate compound (1.20 g, 75%). ¹H NMR (400 MHz,CD₃OD): δ: 7.30 (t, 1H), 7.15 (d, 1H), 7.05 (d, 1H), 3.58 (s, 2H), 3.55(s, 2H), 3.30 (m, 4H), 3.20 (m, 4H).

The reductive amination procedure from Example A1 was followed using4-piperazin-1-yl-indan-2-one to give the title compound. ¹H NMR (400MHz, CDCl₃): δ 7.55 (br s, 1H), 7.42 (d, 1H), 7.25 (t, 1H), 6.98 (d,1H), 6.85 (d, 1H), 6.38 (d, 1H), 4.25 (t, 2H), 3.58 (s, 2H), 3.50 (s,2H), 3.15 (br s, 4H), 2.90 (t, 2H), 2.60 (m, 6H), 2.45 (m, 2H), 1.80 (m,2H), 1.65 (m, 2H). MS ES: m/z 435.19 (M+1)⁺ (Exact mass: 434.23).

Example A62 Synthesis of7-{4-[4-(2,2-Difluoro-indan-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, 4-Bromo-2,2-difluoro-indan, was producedas follows: To a stirred solution of 4-bromo-indan-2-one (5.0 g, 23.70mmol) in dichloromethane (20 mL) cooled to 0° C. was added(diethylamino)sulfur trifluoride (DAST) (9.55 g, 59.30 mmol). Theresulting mixture was stirred at room temperature overnight, dilutedwith additional dichloromethane (50 mL) and quenched with ice-water. Theorganic layer was separated, washed with saturated sodium bicarbonatesolution, water, brine and dried (Na₂SO₄). The solvent was removed invacuo and the residue was purified on a silica gel column using hexanesas eluent to give the first intermediate compound (2.54 g, 46%) as anoil. ¹H NMR (400 MHz, CDCl₃): 7.40 (d, 1H), 7.15 (m, 2H), 3.49 (m, 4H).

A second intermediate compound,4-(2,2-Difluoro-indan-4-yl)-piperazine-1-carboxylic acid tert-butylester, was produced as follows: To a stirred solution of4-bromo-2,2-difluoro-indan (2.41 g, 10.34 mmol) in toluene (65 mL) atroom temperature, was added 1boc-piperazine (2.31 g, 12.42 mmol),tris-(dibenzylideneacetone)di-palladium(0) [Pd₂(dba)₃] (2.37 g, 2.58mmol), tert-2,2′-bis(diphenyl)phosphino-1,1′-binaphthyl (BINAP) (2.90 g,4.66 mmol) and cesium carbonate (4.77 g, 14.63 mmol). The mixture wasdegassed, filled with N₂, degassed and heated at 80° C. for 24 h. Themixture was diluted with ethyl acetate, filtered through a pad of silicagel and the pad was washed with additional amount of ethyl acetate. Thecombined solvent was removed in vacuo and the residue was purified on asilica gel column using hexanes:ethyl acetate (4:1) as eluent to givethe title compound (1.40 g, 40%) as an oil. ¹H NMR (400 MHz, CDCl₃): δ:7.25 (m, 1H), 6.95 (d, 1H), 6.85 (d, 1H), 3.60 (m, 4H), 3.35 (m, 4H),2.95 (m, 4H), 1.45 (s, 9H).

A third intermediate compound, 1-(2,2-Difluoro-indan-4-yl)-piperazine,was produced as follows: A solution of4-(2,2-difluoro-indan4-yl)-piperazine-1-carboxylic acid tert-butyl ester(0.10 g, 0.29 mmol) in methanol (30 mL) was added to a solution ofacetyl chloride (0.35 g, 4.44 mmol) in methanol (50 mL), cooled to 0 oC.The resulting mixture was stirred at room temperature overnight and thesolvent was removed in vacuo. Diethyl ether was added to the residue andthe resulting solid was filtered to give the title compound (0.07 g,87%). 1H NMR (400 MHz, CD3OD): δ: 7.50 (t, 1H), 7.15 (d, 1H), 6.90 (d,1H), 3.45 (m, 4H), 3.35 (m, 4H), 3.15 (m, 4H).

The reductive amination procedure from Example A1 was followed using1-(2,2-difluoro-indan-4-yI)-piperazine to give the title compound (0.360g, 69%). ¹H NMR (400 MHz, CDCl₃): δ: 7.60 (br s,1H), 7.39 (d,1H), 7.25(t,1H), 6.96 (d, 1H), 6.85 (d, 1H), 6.39 (d, 1H), 4.26 (t, 2H), 3.35 (m,4H), 3.15 (br s, 4H), 2.85 (m, 4H), 2.65 (m, 6H), 2.45 (m, 2H), 1.85 (m,1H), 1.65 (m, 1H). MS ES: m/z 457.10 (M+H)⁺ (Exact mass: 456.23).

Example A63 Synthesis of7-{4-[4-(6,7,8,9-Tetrahydro-5H-benzocyclohepten-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,1Nitro-6,7,8,9-tetrahydro-benzocyclohepten-5-one, was produced asfollows: To 250 g (1.56 mmol) of 1-benzosubersone in 5000-mL 4-neckround bottom flask with nitrogen inlet, mechanical stirring, andthermocouple was added 1560 mL of chloroform and 125 g (1.56 mmol) ofammonium nitrate. After the solution was cooled to −15° C., 780 mL (1160g, 5.52 mmol) of trifluoroacetic anhydride was added dropwise keepingthe temperature below −15° C. A white suspension formed. The reactionwas stirred at −15° C. for 1 h and then allowed to warm to roomtemperature and stir for 16 h. The clear orange solution was poured over7.8 L of water and then extracted with two 4000-mL portions ofdichloromethane. The combined organic layers were washed with 4000 mL ofsaturated aqueous sodium bicarbonate and 4000 mL of brine, dried(Na₂SO₄), and concentrated in vacuo to give a mixture of C-8nitration/C-6 nitration/starting material—3:1:1. This material wascombined with material from 64-g and 250-g runs was taken up inapproximately 2.5 L of heptane and brought to near reflux. The solidproduct became an oil on heating. Enough ethyl acetate was added to getthe oil into solution. The solution was allowed to cool to roomtemperature and sit overnight. Crystals, which formed on the sides ofthe flasks, were determined to be mainly the C-8 isomer. The motherliquor was separated and concentrated in vacuo to give C-8 nitration/C-6nitration/starting material—1:1:0.7. The residual solid was purified byflash column chromatography on 3000 g of silica (loaded withdichloromethane and eluted with 15% ethyl acetate-heptane) to give 82.9g of product. This material was recrystallized with heptane-ethylacetate (just enough ethyl acetate to keep the product from oiling out)to give 51.0 g of the title compound as pale yellow needles. Thematerial obtained from the mother liquor was then recrystallized to giveanother 7.1 g of the title compound as yellow needles.

A second intermediate compound ,6,7,8,9-Tetrahydro-5H-benzocyclo-hepten-1-ylamine, was produced, asfollows: TFA (10 mL) was added to a 50 mL flask and cooled in aCO₂/acetone bath. 1Nitro-6,7,8,9-tetrahydro-benzocyclohepten-5-one (1.8g) was added followed by triethylsilane (10 mL). The mixture was warmedto 55° C. After 5 hours, the mixture was evaporated to a residue underhigh vacuum at 70° C. The residue was taken up into hexane, filtered andwashed with 2N HCl. The hexane layer was washed with brine, dried oversodium sulfate and evaporated to an oil (2.7 g), which contained amixture of products. This material was dissolved in methanol and 10%Pd/C (0.6 g) was added. The mixture was pressurized to 50 psi withhydrogen gas for 2 hours, after which the mixture was filtered andevaporated to an oil (2.46 g). The oil was chromatographed on silica gel(gradient of 100% hexane to 60% ethyl acetate) to give the secondintermediate compound as an oil which was crystallized from ether (0.66g), mp 107-111° C.

A third intermediate compound,1-(6,7,8,9-Tetrahydro-5H-benzocyclo-hepten-1-yl)-piperazine, wasproduced as follows: 6,7,8,9-Tetrahydro-5H-benzocyclohepten-1-ylamine(0.617 g) and bis-dichloroethyl amine HCl (1.3 g) were added to asealable tube. Chlorobenzene (3 mL), hexanol (1 mL) anddiisopropylethylamine (2 mL) were added. The solution was warmed to 45°C for 3 hours, then warmed to 95° C overnight. The mixture wasevaporated to give a syrup, which was taken up into dichloromethane andwashed twice with water. The dichloromethane layer was dried over sodiumsulfate and evaporated to an oil (0.88 g). The oil was chromatographedon silica gel and recrystallized from dichloromethane and ether to givethe title compound (0.183 g).

In a manner similar to that of other examples above,6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamine (0.178 g) was coupledby reductive amination to4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowed by typical workup and purification to give the title compoundas the hydrochloride salt (0.109 g). MS: APCl: M+1:449.3 (Exact Mass:448.26).

Example A64 Synthesis of7-[4-(4-Naphthalen-1-yl-priperidin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

7-[4-(4-Naphthalen-1-yl-piperidin-1=yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-onewas produced according to a process similar to that described in ExampleA1, using 4-naphthalen-1-yl-piperidine hydrochloride. Purification byliquid chromatography (5% MeOH/CH₂Cl₂ with 0.8% NH₄0H) gave the titlecompound as a white foam (474 mg, 1.10 mmol). The foam was dissolved inEt₂O/CH₂Cl₂ and 1 N HCl in Et₂O (1.1 mL) was added. The resulting whiteprecipitate was collected by filtration, washed with Et₂O and dried togive a white solid (466 mg). MS: APCl: M+1:430.4 (Exact Mass: 429.24).

Example A65 Synthesis of7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, Trifluoro-methanesulfonic acid7-fluoro-3,4-dihydro-naphthalen-1-yl ester, was produced as follows:7-Fluoro-1-tetralone (1.0 g, 6.10 mmol, prepared according to J Am.Chem. Soc. 1967, 89, 386) was dissolved in tetrahydrofuran (20 mL) thencooled to −78° C. To this solution was added lithiumhexamethyidisilazane (7.32 mL, 7.32 mmol, 1.0 M in tetrahydrofuran) over5 minutes. The mixture was stirred at −78° C. for 1 hour, and thenN-phenyl triflamide (2.62 g, 7.32 mmol) was added in one portion. Themixture was allowed to warm to room temperature and stirred for 2 hours.The mixture was evaporated, dissolved in ethyl acetate (20 mL) andwashed with 1 N sodium hydroxide (20 mL), water (20 mL), and brine (20mL). The organic layer was dried over anhydrous sodium sulfate, filteredand evaporated in vacuo. The crude oil was filtered through a short plugof silica gel, eluting with 9:1 hexanes/ethyl acetate to yield the firstintermediate compound (2.06 g crude, quant.) as a yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 7.20-7.10 (m, 1H), 7.04 (d, 1H), 6.98-6.90 (m, 1H),6.05 (d, 1H), 2.82 (t, 2H), 2.58-2.46 (m, 2H).

A second intermediate compound, Trifluoro-methanesulfonic acid7-fluoro-naphthalen-1-yl ester, was produced as follows:Trifluoro-methanesulfonic acid 7-fluoro-3,4-dihydro-naphthalen-1-ylester (2.06 g, 6.96 mmol) was dissolved in dioxane (20 mL) and2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.37 g, 10.44 mmol) wasadded. The mixture was refluxed for 36 hours and then cooled to roomtemperature. The mixture was evaporated in vacuo to a solid and purifiedby column chromatography (hexanes) to yield the title compound (1.48 g,72%) as a red solid. ¹H NMR (400 MHz, CDCl₃) δ 7.98-7.82 (m, 2H), 7.66(d, 1H), 7.56-7.40 (m, 3H).

A third intermediate compound,4-(7-Fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester, was produced as follows: Trifluoro-methanesulfonic acid7-fluoro-naphthalen-1-yl ester (1.48 g, 5.03 mmol) and 1-Boc-piperazine(1.13 g, 6.04 mmol) were dissolved in toluene (10 mL) and the mixturewas degassed for 30 minutes. To this was added2-(dicyclohexylphosphino)-biphenyl (176 mg, 0.50 mmol), palladiumacetate (113 mg, 0.50 mmol), and sodium tert-butoxide (677 mg, 7.04mmol). The mixture was stirred at 80° C. for 16 hours and then cooled toroom temperature. The mixture was washed with water (20 mL) and brine(20 mL), dried over anhydrous sodium sulfate, filtered and concentratedin vacuo. The crude oil was filtered through a short plug of silica gel,eluting with 3:1 hexanes/ethyl acetate to yield the title compound (900mg, 54%) as a brown oil.

A fourth intermediate compound, 1-(7-Fluoro-naphthalen-1-yl)-piperazine,was produced as follows:4-(7-Fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester (900 mg, 2.73 mmol) was dissolved in dichloromethane (10 mL) andtrifluoroacetic acid (2 mL). The mixture was stirred at room temperaturefor 3 hours then diluted with diethyl ether. The solid was filtered offand washed with diethyl ether (2-20 mL) to yield the title compound asthe TFA salt (415 mg, 1.21 mmol, 44%) as a grey powder. ¹NMR (400 MHz,dmso-d₆) δ 8.80 (s, 1H), 8.04 (t, 1H), 7.82 (d, 1H), 7.58 (d, 1H), 7.44(t, 2H), 7.24 (d, 1H), 3.40-3.30 (m, 4H), 3.20-3.00 (m, 4H).

The reductive amination procedure from Example A1 was followed using1-(7-fluoro-naphthalen-1-yl)-piperazine to give the title compound. ¹NMR(400 MHz, dmso-d₆) δ 10.25 (s, 1H), 8.00 (t, 1H), 7.80-7.60 (m, 2H),7.46-7.40 (m, 3H), 7.20 (d, 1H), 6.38 (d, 1H), 4.20 (t, 2H), 3.06-2.90(m, 4H), 2.80 (t, 2H), 2.80-2.60 (m, 4H), 2.50-2.40 (m, 4H), 1.80-1.70(m, 2H), 1.64-1.55 (m, 2H), MS ES+449.31 (M+1)⁺ (Exact mass: 448.23).

Example A66 Synthesis of7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, 8-Bromo-naphthalen-1-ylamine, wasproduced as follows: 8-Bromo-naphthalene-1carboxylic acid (10.0 g, 39.8mmol) was taken up in CHCl₃ (60 mL) and conc. H₂SO₄ (20 mL) were added.The mixture was stirred at 45° C. until all the compound was dissolved.NaN₃ (15.52 g, 240.0 mmol, 6.0 equiv) was then added in portions, eachsuccessive portion was added after the effervescence resulting from theprevious addition had subsided. The mixture was stirred for 2 h at 45°C. and added to water (100 mL). The mixture was made alkaline withaqueous ammonia and extracted with dichloromethane (4×30 mL). Thecombined extracts were dried over Na₂SO₄ and evaporated to give thetitle compound as a dark crystalline solid (8.5 g, 96%). ¹HNMR (400 MHz,CDCl₃): δ 7.70 (d, 1H), 7.65 (d, 1H), 7.30 (d, 2H), 7.05 (t, 1H), 6.65(m, 1H), 5.20 (br s, 2H). MS (ES+): 221.99 (M⁺), 223.99 (M⁺²).

A second intermediate compound, 1-Bromo-8-fluoro-naphthalene, wasproduced as follows: To a cooled solution of8-bromo-naphthalen-1-ylamine (8.0 g, 36.0 mmol) in THF (10 mL) was added48% HBF₄ (50 mL) at 0° C. and the mixture was stirred for 10 min. Asolution of NaNO₂ (7.5 g, 108.1 mmol, 3.0 equiv) in water (20 mL) wasadded and the stirring was continued for 1 h at 0° C., then NaBF₄ (20.0g, 180.0 mmol, 5.0 equiv) was added. The mixture was allowed to warm toroom temperature and stir for 1 h. The reaction was filtered and thesolid was washed with ether and dried overnight under high vacuum togive a gray solid. This solid was taken up in chlorobenzene (30 mL) andrefluxed for 3 h. The solvent was removed under reduced pressure and thedark residue was triturated with hexane. The yellow colored hexane layerwas decanted and trituration with hexane was repeated several timesuntil the hexane layer became colorless. The combined hexane portionswere concentrated to give the second intermediate compound as a darkyellow oil (5.6 g, 69%). ¹HNMR (400 MHz, CDCl₃): δ 7.78 (m, 2H), 7.60(d, 1H), 7.35-7.15 (m, 3H).

A third intermediate compound, 1-(8-Fluoro-naphthalen-1-yl)-piperazine,was produced as follows: A solution of Pd(OAc)₂ (0.25 g, 1.11 mmol, 0.1equiv)) and dicyclohexylphosphino-biphenyl (0.39 g, 1.11 mmol, 0.1equiv) in toluene (20 mL) was degassed by bubbling N₂ gas for 1 h.1Bromo-8-fluoro-naphthalene (2.5 g, 11.1 mmol) in toluene (10 mL) and1-Boc-piperazine (2.5 g, 13.3 mmol, 1.2 equiv) were added followed byNaOtBu (1.6 g, 16.66 mmol, 1.5 equiv). The mixture was stirred at 80° C.for 18 h. The solvent was removed under reduced pressure and the residuewas taken in dichloromethane and filtered through a celite pad. Thecelite was rinsed with dichloromethane and the combined filtrates wereconcentrated. The residue was purified by silica gel chromatography (20%ethyl acetate in hexane) to give4-(8-fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester as a dark oil (1.4 g, 38%). ¹HNMR (400 MHz, CDCl₃): δ 7.60 (d,1H), 7.50 (d, 1H), 7.40 (m, 1H), 7.10 (m, 2H), 6.95 (d, 1H), 4.50-4.00(br s, 2H), 3.40-3.20 (m, 4H), 2.80-2.60 (m, 2H), 1.50 (s, 9H). MS(ES+): 331.08 (M+H)⁺.

4-(8-Fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester (1.4 g, 4.2 mmol) was dissolved in dichloromethane (10 mL) and TFA(10 mL) was added at 0° C. The mixture was allowed to warm to roomtemperature and stir for 1 h. The solvents were removed under reducedpressure and the residue was purified by silica gel chromatography (5%methanol in dichloromethane) to give the third intermediate compound asa TFA salt (1.3 g, 89%). ¹HNMR (400 MHz, CDCl₃): δ 7.65-7.58 (m, 2H),7.40 (m, 2H), 7.10-7.00 (m, 2H), 3.60-3.40 (m, 6H), 3.40-3.20 (m, 2H).MS (ES+): 231.11 (M+H)⁺.

The reductive amination procedure from Example A1 was followed using1-(8-fluoro-naphthalen-1-yl)-piperazine. 1HNMR (400 MHz, CDCl3): δ 7.60(m, 2H), 7.50 (m, 1H), 7.40 (m, 3H), 7.10-7.00 (m, 2H), 6.28 (d, 1H),4.25 (t, 2H), 3.40-3.30 (m, 2H), 3.05-2.80 (m, 6H), 2.65 (t, 2H),2.60-2.40 (m, 4H), 1.80-1.60 (m, 4H). MS (ES+): 449.19 (M+H)⁺ (Exactmass: 448.23).

Example A67 Synthesis of7-{4-[4-(6-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, 6-Fluoro-1-tetralone, was produced asfollows: 6-Amino-3,4-dihydro-2H-naphthalen-1-one (6.45 g, 40.1 mmol) wasdissolved in a mixture of hydrochloric acid (9 mL) and water (6 mL) andcooled to 0° C. A solution of sodium nitrite (2.90 g, 42.0 mmol) inwater (4 mL) was added dropwise to the mixture and tetrafluoroboric acid(8.0 g, 44.0 mmol, 5.71 mL, 48% in water) was added. The mixture wasallowed to stand at 0° C. for 30 minutes and then cooled to −30° C. Theprecipitate was filtered off and rinsed with cold methanol (10 mL), andthen with cold diethyl ether (10 mL) to yield the diazonium salt (6.0 g,58%) as a brown solid. ¹H NMR (400 MHz, dmso-d₆) δ 8.70 (s, 1H), 8.59(d, 1H), 8.30 (d, 1H), 3.10 (t, 2H), 2.78 (t, 2H), 2.20-2.06 (m, 2H).

The diazonium salt (6.0 g, 23.3 mmol) was dried overnight in vacuo, thensuspended in toluene (60 mL) and stirred at 110° C. for 1 hour. Themixture was cooled to room temperature and the liquid was decanted fromthe insoluble tar. The organic mixture was washed with water (20 mL), 1N sodium hydroxide (20 mL), and water (20 mL). The organic layer wasdried over anhydrous magnesium sulfate, filtered and concentrated invacuo. The crude oil was purified by column chromatography (8:1,hexanes/ethyl acetate) to yield the first intermediate compound (2.87 g,76%) as a light red oil. ¹H NMR (400 MHz, CDCl₃) δ 8.04 (t, 1H),7.00-6.84 (m, 2H), 2.95 (t, 2H), 2.62 (t, 2H), 2.20-2.02 (m, 2H).

A second intermediate compound, Trifluoro-methanesulfonic acid6-fluoro-3,4-dihydro-naphthalen-1-yl ester, was produced as follows:6-Fluoro-1-tetralone (1.00 g, 6.10 mmol) was dissolved intetrahydrofuran (20 mL) and cooled to −78° C. Lithiumhexamethyidisilazane (7.32 mmol, 7.32 mL, 1.0 M solution intetrahydrofuran) was added dropwise and the mixture was stirred at −78°C. for 1 hour. N-Phenyl triflamide (2.62 g, 7.32 mmol) intetrahydrofuran (5 mL) was added and the mixture was allowed to warm toroom temperature over 1.5 hours and then was poured into water (20 mL).The mixture was extracted with ethyl acetate (20 mL) and the organiclayer was washed with water (2×20 mL), 1 N sodium hydroxide (20 mL), andbrine (20 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The crude oil was filteredthrough a short plug of silica gel, eluting with hexanes to yield thesecond intermediate compound (1.69 g, 94%) as a light brown oil. ¹H NMR(400 MHz, CDCl₃) δ 7.38-7.28 (m, 1H), 7.00-6.84 (m, 2H), 5.99 (t, 1H),2.84 (t, 2H), 2.60-2.50 (m, 2H).

A third intermediate compound, Trifluoro-methanesulfonic acid6-fluoro-naphthalen-1-yl ester, was produced as follows:Trifluoro-methanesulfonic acid 6-fluoro-3,4-dihydro-naphthalen-1-ylester (1.69 g, 5.72 mmol) was dissolved in dioxane (20 mL) and2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.95 g, 8.57 mmol) was added.The mixture was heated at reflux for 36 hours and then additional2,3-dichloro-5,6-dicyano-1,4-benzoquinone (649 mg, 2.86 mmol) was addedand the mixture refluxed for another 6 hours. The mixture was cooled toroom temperature, evaporated to a solid and loaded onto a short plug ofsilica gel, eluting with hexanes to yield the first intermediatecompound (1.24 g, 74%) as a yellow semi-solid. ¹H NMR (400 MHz, CDCl₃) δ8.10-8.05 (m, 1H), 7.80 (d, 1H), 7.60-7.45 (m, 2H), 7.45-7.38 (m, 2H).

A fourth intermediate compound, 1-(6-Fluoro-naphthalen-1-yl)-piperazine,was produced as follows: Trifluoro-methanesulfonic acid6-fluoro-naphthalen-1-yl ester (1.24 g, 4.23 mmol) and 1-Boc-piperazine(946 mg, 5.08 mmol) were dissolved in toluene (15 mL) and the mixturewas degassed for 30 minutes. To this was added2-(dicyclohexylphosphino)-biphenyl (148 mg, 0.42 mmol), palladiumacetate (95 mg, 0.42 mmol), and sodium tert-butoxide (569 mg, 5.92mmol). The mixture was stirred at 80° C. for 30 minutes, then cooled toroom temperature, washed with water (20 mL) and brine (20 mL), driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Thecrude oil was filtered through a short plug of silica gel, eluting with3:1 hexanes/ethyl acetate to yield crude4-(6-fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester as a brown oil. The crude oil was dissolved in a mixture ofdichloromethane (5 mL) and trifluoroacetic acid (5 mL) and stirred atroom temperature for 4 hours. The mixture was evaporated in vacuo anddiethyl ether (30 mL) was added. The grey precipitate was filtered offand rinsed with diethyl ether (20 mL) to yield the fourth intermediatecompound as the TFA salt (755 mg, 52%) as a grey solid. ¹H NMR (400 MHz,dmso-d₆) δ 8.80 (s, 1H), 8.24-8.18 (m, 1H), 7.72 (d, 1H), 7.68 (d, 1H),7.50 (t, 1H), 7.40 (t, 1H), 7.18 (d, 1H), 3.40-3.10 (m, 8H).

The reductive amination procedure from Example A1 was followed using1-(6-fluoro-naphthalen-1-yl)-piperazine to give the title compound. ¹HNMR (400 MHz, dmso-d₆) δ 10.20 (s, 1H), 8.22-7.98 (m, 1H), 7.75 (d, 1H),7.65 (d, 1H), 7.54-7.48 (m, 2H), 7.44 (t, 1H), 7.20 (d, 1H), 6.40(d,1H), 4.24 (t, 2H), 3.70-3.10 (m, 10H), 2.80 (t, 2H), 2.44 (t, 2H),1.95-1.76 (m, 4H), MS ES+ 449.25 (M+H)⁺ (Exact mass: 448.23).

Example A68 Synthesis of7-{4-[4-(5-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, 5-Bromo-naphthalene-1-carboxylic acid,was produced, as follows: To a suspension of naphthalene-1-carboxylicacid (20.14 g, 0.12 mmol) in HOAc (100 mL) was added Br₂ (6.60 mL, 0.13mmol). The mixture was heated at 110° C. for 48 h and cooled to roomtemperature. It was filtered, the pad was washed with hexane and driedto give the first intermediate compound (18.0 g) as a grey solid in 62%.¹H NMR (400 MHz, CDCl₃): δ 13.40 (br s, 1H), 8.90 (d, J=6.2 Hz, 1H),8.42 (d, J=6.0 Hz, 1H), 8.25 (d, J=5.4 Hz, 1H), 8.00 (d, J=5.3 Hz, 1H),7.80 (m, 1H), 7.60 (m, 1H).

A second intermediate compound, 5-Bromo-naphthalen-1-ylamine, wasproduced as follows: To a solution of 5-bromo-naphthalene-1carboxylicacid (10 g, 40 mmol) in t-BuOH (150 mL) was added Et₃N (13.6 mL, 80mmol) and DPPA (10.5 mL, 48 mmol) successively. After the mixture wasstirred at room temperature for 1 h, it was refluxed for 16 h. Thesolvent was then removed and the residue was purified by chromatographyon silica gel to give (5-bromo-naphthalen-1-yl)-carbamic acid tert-butylester (8.4 g, 65%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.60 (d,J=6.8 Hz, 1H), 8.55 (d, J=6.6 Hz, 1H), 8.50 (d, J=6.2 Hz, 1H), 8.40 (d,J=6.4 Hz,1H), 8.20 (t, J=6.7 Hz,1H), 8.10 (t, J=6.3 Hz,1H).

The material obtained in the last step was dissolved in dichloromethane(150 mL) and trifluoroacetic acid (15 mL) was added. The resultingmixture was stirred under reflux for 2 h. The solvent was removed. Theresidue was washed with hexane to give a white solid, which wassuspended in dichloromethane (150 mL) and treated with aqueous KOH (50mL containing 15 g KOH). The mixture was stirred at room temperature for30 min. The organic layer was separated and the aqueous layer wasextracted with dichloromethane (2×50 mL). The combined organic phaseswere dried over Na₂SO4 and concentrated to give the second intermediatecompound (5.13 g, 85%) as a purple solid. ¹H NMR (400 MHz, CDCl₃): δ8.80 (m, 2H), 7.70 (d, J=7.4 Hz, 2H), 7.40 (t, J=6.2 Hz, 1H), 7.20 (t,J=6.0 Hz, 1H), 6.80 (d, J=6.2 Hz, 1H).

A third intermediate compound, 1-Bromo-5-fluoro-naphthalene. Wasproduced as follows: To a cooled (0° C.) solution of5-bromo-naphthalen-1-ylamine (1.0 g, 4.52 mmol) in THF (1 mL) was added48% HBF₄ (10 mL) followed by a solution of NaNO₂ (0.49 g, 13.58 mmol, 3eq) in water (2 mL). After the addition was over, the mixture was keptstirring at 0° C. for 1 h and NaBF₄ (2.49 g, 22.6 mmol, 5 eq) was added.The mixture was allowed to warm up to room temperature and filtered. Thesolid was washed with ether and dried overnight under high vacuum togive a green solid, which was suspended in xylene (5 mL) and refluxedfor 1 h. The resulting mixture was subjected to chromatography on silicagel to give the third intermediate compound (480 mg) as a yellow solidin 47% yield for two steps. ¹H NMR (400 MHz, CDCI₃): δ 8.17 (d, J=7.4Hz, 1H), 8.10 (d, J=7.4 Hz 1H), 7.90 (d, J=6.2 Hz, 1H), 7.55 (m, 1H),7.40 (t, J=6.4 Hz, 1H), 7.20 (m, 1H).

A fourth intermediate compound, 1-(5-Fluoro-naphthalen-1-yl)-piperazine,was produced as follows: A solution of Pd(OAc)₂ (0.31 mg, 1.38 mmol) anddicyclohexylphosphrous-diphenyl (0.48 mg, 1.38 mmol) was degassed bybubbling N₂ for 20 min. 1-Bromo-5-fluoro-naphthalene (3.10 g, 13.8 mmol)and 1-Boc-piperazine (3.08 g, 16.6 mmol) were added followed by NaOt-Bu(1.86 g, 19.3 mmol). The mixture was warmed up to 80° C. and kept atthis temperature for 16 h. The solvent was removed under reducedpressure and the residue was dissolved in 6 N HCl (60 mL) and washedwith ether (3×50 mL). The aqueous phase was basified with solid KOH topH=11, it was then extracted with EtOAc (3×100 mL). The combined organicphases were dried over Na₂SO₄ and concentrated to give the fourthintermediate compound (2.10 g, 66%) as a brown oil. ¹H NMR (400 MHz,CDCl₃): 67 8.00 (d, J=6.5 Hz, 1H), 7.80 (d, J=6.3 Hz, 1H), 7.45 (m, 1H),7.40 (m, 1H), 7.10 (m, 2H), 3.40-3.10 (m, 8H).

The reductive amination procedure from Example A1 was followed using1-(5-fluoro-naphthalen-1-yl)-piperazine to give the first intermediatecompound. ¹H NMR (400 MHz, CDCI₃): δ 6 8.00 (d, J=6.2 Hz, 1H), 7.80 (d,J=6.0 Hz, 1H), 7.60 (br s, 1H), 7.55 (t, J=7.0 Hz, 1H), 7.42 (m, 2H),7.10 (m, 2H), 6.40 (d, J=6.3 Hz, 1H), 4.25 (t, J=4.5 Hz, 2H), 3.20 (brs, 4H), 2.90-2.40 (m, 10H), 1.90-1.70 (m, 4H). Elemental Analysis:calculated for C₂₆H₂₉FN₄O₂.0.5H₂O: C, 68.27; H, 6.35; N, 12.25. Found:C, 68.22; H, 6.50; N, 11.85.

Example A69 Synthesis of7-{4-[4-(4-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, 1-(4-Fluoro-naphthalen-1-yl)-piperazine,was produced as follows: A mixture of dicyclohexylphosphino biphenyl(0.155 g, 0.444 mmol, 0.1 mmol) and palladium acetate (0.099 g, 0.444mmol, 0.1 equiv) in dry toluene (15 mL) was bubbled with N₂ gas for twohours. To the resultant clear solution was added 1-bromo-4-fluoronaphthalene (1.0 g, 4.44 mmol, 1.0 equiv) followed by 1-Boc-piperazine(1.0 g, 5.33 mmol, 1.2 equiv). To this mixture was added NaO^(t)Bu(0.600 g, 6.22 mmol, 1.4 equiv) and the reaction mixture was stirred at80° C. overnight. The reaction mixture was cooled to room temperature,and the solvent was removed under reduced pressure. The residue wastaken up in CH₂Cl₂, filtered through a celite bed, and then rinsed withCH₂Cl₂. The combined filtrates were concentrated and purified by columnchromatography on silica (20% EtOAc in hexane).4-(4-Fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester (1.4 g, impure) was obtained as a dark viscous liquid, which wasused in the next step without further purification. ¹H NMR: (400 MHz,CDCl₃) δ 8.25 (m, 1H), 8.05 (m, 1H), 7.55 (m, 2H), 7.05-6.80 (m, 2H),4.00 (br s, 4H), 3.00 (br s, 4H), 1.45(s, 9H). MS: ES+ 331.13 (M+H)⁺(Exact mass: 330.17).

To a solution of 4-(4-fluoro-naphthalen-1-yl)-piperazine-1-carboxylicacid tert-butyl ester (1.1 g, 3.33 mmol) in CH₂Cl₂ (10 mL) was added TFA(10 mL) at 0° C. The reaction mixture was warmed to room temperature andstirred for one hour. Solvents were removed and the residue was purifiedby column chromatography on silica (10% MeOH in CH₂Cl₂) to afford thefirst intermediate compound (0.90 g, 78%) as a pale brown crystallinesolid. ¹H NMR: (400 MHz, DMSO-d₆) δ 9.0 (br s, 2H), 8.28 (m, 1H), 8.08(m, 1H), 7.65 (m, 2H), 7.30 (m, 1H), 7.08 (m, 1H), 3.45 (br s, 4H), 3.20(br s, 4H). MS: ES+ 231.09 (M+H)⁺ (Exact mass: 230.12).

The reductive amination procedure from Example A1was followed using1-(4-fluoro-naphthalen-1-yl)-piperazine to give the title compound. ¹HNMR: (400 MHz, CDCl₃) δ 8.25 (m, 1H), 8.10 (m, 1H), 7.65 (br s, 1H),7.55 (m, 2H), 7.38 (d, 1H), 7.10-6.95 (m, 2H), 6.35 (d, 1H), 4.25 (t,2H), 3.10-3.00 (br s, 4H), 2.90-2.40 (m, 10H), 1.85-1.55 (m, 4H). MS:ES+ 449.18 (M+H)⁺ (Exact mass: 448.23).

Example A707-{4-[4-(3-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate, 3-Fluoro-naphthalene-1-carboxylic acid methylester, was produced as follows: An ice-cold mixture of3-amino-naphthalene-1-carboxylic acid methyl ester (1.76 g, 8.75 mmol)in tetrahydrofuran (2 mL) was treated with 48% tetrafluoroboric acid (20mL) followed by sodium nitrite (1.81 g, 26.20 mmol) in water (4 mL). Thesuspension was stirred for 1 hour at 0° C., then sodiumtetrafluoroborate (4.80 g, 43.70 mmol) was added. The suspension waswarmed to room temperature and stirred for 30 minutes. The greendiazonium salt was collected by vacuum filtration, rinsed with diethylether and dried under high vacuum overnight. The solid was diluted withchlorobenzene (10 mL) and then refluxed for 1 hour. The brown solutionwas cooled to room temperature, quenched with water and extracted withdichloromethane. The extracts were dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo to a brown oil. The oil was purified by columnchromatography (5:1, hexanes/ethyl acetate) to afford the firstintermediate compound (0.892 g, 50%) as a yellow liquid. ¹H NMR (400MHz, CDCl₃) δ 8.89 (d, 1H), 8.00-7.94 (m, 1H), 7.85-7.78 (m, 1H),7.70-7.62 (m, 1H), 7.60-7.52 (m, 2H), 4.00 (s, 3H).

A second intermediate compound, (3-Fluoro-naphthalen-1-yl)-carbamic acidtert-butyl ester, was produced as follows: A mixture of3-fluoro-naphthalene-1-carboxylic acid methyl ester (4.47 g, 21.90 mmol)in 2N KOH (15 mL, 30 mmol) and methanol (60 mL) was refluxed for 2hours. The solution was cooled, then concentrated under reducedpressure. The residue was diluted with water and acidified to pH 1 with3N HCl. A solid precipitated out of solution and the suspension wasdiluted with ethyl acetate. The organic layer was separated and theaqueous layer was extracted with ethyl acetate. The combined extractswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo toafford the carboxylic acid (4.08 g, 98%) as a yellow solid.

A mixture of 3-fluoro-naphthalene-1-carboxylic acid (3.98 g, 21 mmol) indry tert-butanol (80 mL) was treated with triethylamine (6.2 mL, 44mmol) followed by diphenylphosphoryl azide (5.60 mL, 26 mmol). Theyellow solution was refluxed overnight, then cooled and concentratedunder vacuum. The residue was purified by column chromatography (7:1,hexanes/ethyl acetate) to afford the second intermediate compound (4.78g, 87%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 6 7.96-7.87 (m,1H), 7.84-7.75 (m, 2H), 7.56-7.43 (m, 2H), 7.21 (d, 1H), 7.03 (br s,1H), 1.48 (s, 9H).

A third intermediate compound, 1-(3-Fluoro-naphthalen-1-yl)-piperazine,was produced as follows: A solution of(3-fluoro-naphthalen-1-yl)-carbamic acid tert-butyl ester (4.78 g, 18.30mmol) in dichloromethane (30 mL) and trifluoroacetic acid (10 mL) wasrefluxed for 2 hours. The mixture was diluted with diethyl ether and thesolid that precipitated out was collected by vacuum filtration as theTFA salt (2.137 g). The filtrate was neutralized with 2N KOH andextracted with dichloromethane. The extracts were dried over anhydrousNa₂SO₄, filtered and concentrated to a brown residue. The residue waspurified by column chromatography (5:1, hexanes/ethyl acetate) to afford3-fluoro-naphthalen-1-ylamine (0.967 g, 33%). The TFA salt (2.137 g) wasstirred in a heterogeneous solution of 2N KOH (10 mL) in dichloromethane(20 mL). The organic layer was separated and the aqueous layer wasextracted with dichloromethane. The combined extracts were dried overanhydrous Na₂SO₄, filtered and concentrated to afford an additionalamount of 3-fluoro-naphthalen-1-ylamine (1.193 g, 40%). ¹H NMR (400 MHz,CDCl₃) δ 7.78-7.64 (m, 2H), 7.48-7.42 (m, 1H), 7.41-7.34 (m, 1H), 6.90(d, 1H), 6.54 (d, 1H), 4.30 (br s, 2H).

A solution of 3-fluoro-naphthalen-1-ylamine (1.00 g, 6.20 mmol), sodiumiodide (0.465 g, 3.10 mmol), diisopropylethylamine (0.30 mL, 3.10 mmol)and bis(2-chloroethyl)amine hydrochloride (1.218 g, 6.82 mmol) inchlorobenzene (10 mL) and 1-hexanol (1 mL) was heated at 150° C.overnight. The solvent was removed from the brown solution by vacuumdistillation and the residue was cooled to room temperature. The residuewas diluted with hexanes/diethyl ether (1:1) and then the solvent wasdecanted. This was repeated, then the solid was collected by vacuumfiltration. The brown solid was diluted with methanovchloroform andabsorbed onto SiO₂, then loaded onto a column for chromatography(methanoVammonium hydroxide/chloroform, 8:1:91) to afford a brown oil.The oil was triturated with diethyl ether to afford the thirdintermediate compound (0.173 g, 12%), as a brown solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.20 (br s, 1H), 8.10 (d, 1H), 7.88 (d, 1H), 7.60-7.41 (m,2H), 7.02 (d, 1H), 3.20 (br s, 4H), 3.05 (br s, 4H).

The reductive amination procedure from Example A1 was followed using1-(3-fluoro-naphthalen-1-yl)-piperazine to give the title compound. ¹HNMR (400 MHz, CDCl₃) δ 8.12 (d, 1H), 7.74 (d, 1H), 7.55 (br s, 1H),7.50-7.39 (m, 2H), 7.37 (d, 1H), 7.14 (dd, 1H), 6.86 (dd, 1H), 6.36 (d,1H), 4.24 (t, 2H), 3.16 (br s, 4H), 2.87 (t, 2H), 2.75 (br s, 4H), 2.64(t 2H), 2.54 (t, 2H), 1.88-1.78 (m, 2H), 1.78-1.68 (m, 2H); ES MS:449.12 (M+H)⁺ (Exact mass: 448.23).

Example A71 Synthesis of7-{4-[4-(2-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate, 1-Bromo-naphthalen-2-ylamine, was produced asfollows: To a solution of naphthalen-2-ylamine (1.03 g, 7.2 mmol) in DMFwas added NBS (1.54 g, 8.6 mmol, 1.2 eq). The mixture was heated at 110°C. for 2 h, cooled to room temperature, taken up in EtOAc (150 mL) andwashed with water (3×50 mL). The organic phase was dried over Na₂SO₄ andconcentrated. The residue was purified by chromatography on silica gelto give compound the first intermediate compound (1.12 g, 70%) as a redsolid. ¹NMR (400 MHz, CDCl₃): δ 8.05 (d, J=5.8 Hz, 1H), 7.70 (d, J=6.0Hz, 1H), 7.65 (d, J=6.0 Hz, 1H), 7.58 (t, J=5.2 Hz, 1H), 7.30 (t, J=5.1Hz, 1H), 7.00 (d, J=6.1 Hz, 1H), 4.40 (br s, 2H).

A second intermediate compound, 1-Bromo-2-fluoro-naphthalene, wasproduced as follows: To a cooled (0° C.) solution of1-bromo-naphthalen-2-ylamine (1.0 g, 4.52 mmol) in THF (1 mL) was added48% HBF₄ (10 mL) followed by a solution of NaNO₂ (0.49 g, 13.58 mmol, 3eq) in water (2 mL). After the addition was over, the mixture was keptstirring at 0° C. for 1 h and NaBF₄ (2.49 g, 22.6 mmol, 5 eq) was added.The mixture was allowed to warm to room temperature and was filtered.The solid was washed with ether and dried overnight under high vacuum togive the diazonium salt as a green solid, which was used in the nextstep. ¹H NMR (400 MHz, CDCl₃): δ 8.60 (d, J=6.8 Hz, 1H), 8.55 (d, J=6.6Hz, 1H), 8.50 (d, J=6.2 Hz, 1H), 8.40 (d, J=6.4 Hz, 1H), 8.20 (t, J=6.7Hz, 1H), 8.10 (t, J=6.3 Hz, 1H).

The material obtained in the last step was suspended in xylene (5 mL)and refluxed for 1 h. The resulting mixture was subjected tochromatography on silica gel to give the second intermediate compound(480 mg, 47%) as a yellow solid for two steps. ¹H NMR (400 MHz, CDCl₃):δ 8.22 (d, J=7.4 Hz, 1H), 7.80 (m, 2H), 7.60 (t, J=6.2 Hz, 1H), 7.50 (t,J=6.0 Hz, 1H), 7.30 (t, J=7.6 Hz, 1H).

A third intermediate compound, 1-(2-Fluoro-naphthalen-1-yl)-piperazine,was produced as follows: A solution of Pd(OAc)₂ (44.8 mg, 0.2 mmol) and2-(dicyclohexylphosphino)biphenyl (70.0 mg, 0.2 mmol) was degassed bybubbling N₂ for 20 min. 1-Bromo-2-fluoro-naphthalene (0.448 g, 2 mmol)and 1-Boc-piperazine (0.446 g, 2.4 mmol) were added followed by theaddition of NaO^(t)Bu (0.27 g, 2.8 mmol). The mixture was warmed up to80° C. and kept at this temperature for 16 h. The solvent was removedunder reduced pressure and the residue was purified by chromatography onsilica gel to give 4-(2-fluoro-naphthalen-1-yl)-piperazine-1-carboxylicacid tert-butyl ester (0.24 g, 40%).

A mixture of 4-(2-fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acidtert-butyl ester (1.05 g, 2.83 mmol) and TFA (1 mL) in dichloromethane(10 ml) was refluxed for 2 h. The solvent was removed under reducedpressure to give a black solid (1.05 g), which was dissolved indichloromethane (2 mL) and ether was added to precipitate the thirdintermediate compound (0.36 g) as the TFA salt. ¹NMR (400 MHz, CDCl₃): δ8.75 (d, J=6.5 Hz, 1H), 8.00 (d, J=6.3 Hz, 1H), 7.90 (m, 1H), 7.62 (m,1H), 7.58 (m, 1H), 7.42 (t, J=6.6 Hz, 1H), 3.60-3.10 (m, 8H).

The reductive amination procedure from Example A1 was followed using1-(2-fluoro-naphthalen-1-yl)-piperazine to give the title compound. ¹HNMR (400 MHz, CDCl₃): δ 8.40 (d, J=6.2 Hz, 1H), 7.80 (d, J=6.0 Hz, 1H),7.60 (m, 1H), 7.55 (m, 2H), 7.42 (m, 1H), 7.37 (d, J=5.9 Hz, 1H), 7.20(m, 1H), 6.35 (d, J=6.3 Hz, 1H), 4.25 (t, J=4.5 Hz, 2H), 3.50 (m, 2H),3.10 (m, 1H), 2.95 (m, 2H), 2.85 (t, J=6.0 Hz, 2H), 2.65 (t, J=7.2 Hz,2H), 2.50 (m, 2H), 2.40 (m, 2H), 1.85 (m, 2H), 1.75 (m, 2H).

Example A72 Synthesis of7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, Trifluoro-methanesulfonic acid6,7-difluoro-3,4-dihydro-naphthalen-1-yl ester, was produced as follows:To a cooled (−78° C.) solution of6,7-difluoro-3,4-dihydro-2H-naphthalen-1-one (3.64 g, 20 mmol,Tetrahedron Lett. 2003, 44, 4007) in THF (40 mL) was added LiHMDS (24mL, 24 mmol) over 10 min. The resulting mixture was stirred at −78° C.for 1 h and a solution of N-phenyltrifluoromethanesulfonimide (8.59 g,24 mmol) in THF (20 mL) was added. The mixture was stirred at −78° C.for another 3 h, quenched with H₂O and extracted with EtOAc (3×50 mL).The combined organic phases were dried and concentrated to give thefirst intermediate compound (6.28 g, 100%). ¹H NMR (400 MHz, CDCl₃): δ7.20 (m, 1H), 7.00 (m, 1H), 6.05 (t,1H), 2.80 (m, 2H), 2.50 (m, 2H).

A second intermediate compound, Trifluoro-methanesulfonic acid6,7-difluoro-naphthalen-1-yl ester, was produced as follows: A mixtureof trifluoro-methanesulfonic acid6,7-difluoro-3,4-dihydro-naphthalen-1-yl ester (6.28 g, 20 mmol) and DDQ(9.08 g, 40 mmol) in dioxane (60 mL) was refluxed for 24 h and thencooled to RT. The reaction mixture was partitioned between hexanes andwater. The organic layer was washed with water, dried and concentrated.The residue was passed through a pad of celite eluting with hexane whichgave the second intermediate compound (4.38 g, 70%) as a yellow solid.¹H NMR (400 MHz, CDCl₃): δ 7.80 (m, 2H), 7.70 (m, 1H), 7.50 (m, 2H).

A third intermediate compound,1-(6,7-Difluoro-naphthalen-1-yl)-piperazine, was produced as follows:Nitrogen gas was bubbled through a solution of trifluoro-methanesulfonicacid 6,7-difluoro-naphthalen-1-yl ester (4.38 g, 14.04 mmol),1-Boc-piperazine (3.18 g, 16.85 mmol), Pd(OAc)₂ (0.31 g, 1.4 mmol) and2-dicyclohexylphosphino biphenyl (0.49 g, 1.4 mmol) in toluene (40 mL)for 10 min. NaOtBu (1.89 g, 19.66 mmol) was added. The resulting mixturewas heated at 80° C. for 2 h, cooled to RT, diluted with EtOAC (40 mL)and filtered through a pad of celite. The filtrate was concentrated andthe residue was purified by chromatography on silica gel to give4-(6,7-difluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester.

To a solution of the4-(6,7-difluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester (1.15 g) in MeOH (10 mL) was added conc. HCl (4 mL). The resultingmixture was stirred at room temperature for 16 h and concentrated undervacuum. The solid obtained was washed with a small amount of MeOH andether and dried to give the third intermediate compound (0.43 g, 11% intwo steps). ¹H NMR (400 MHz, DMSO-d₆): δ 9.30 (br s, 2H), 8.10 (m, 2H),7.70 (d, 1H), 7.50 (t, 1H), 7.30 (d, 1H), 3.40 (br s, 4H), 3.20 (br s,4H).

The reductive amination procedure from Example A1 was followed using1-(6,7-difluoro-naphthalen-1-yl)-piperazine to give the title compound(0.25 g, 75%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.30 (br s, 2H), 8.05 (m,2H), 7.70 (d, 1H), 7.50 (m, 2H), 7.26 (d, 1H), 6.40 (d, 1H), 4.22 (t,2H), 3.60 -3.10 (m, 10H), 2.80 (m, 2H), 2.50 (m, 2H), 1.90-1.70 (m, 4H).

Example A73 Synthesis of7-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1.8]naththyridin-2-one

A first intermediate compound,4-(7-Methoxy-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester, was produced as follows:4-(7-Hydroxy-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester (2.0 g, 6.10 mmol) was dissolved in dimethylsulfoxide (7 mL) andsodium hydroxide (366 mg, 9.14 mmol) was added. The mixture was stirredfor 5 minutes and then methyl iodide (1.73 g, 0.76 mL, 12.20 mmol) wasadded. The reaction was stirred at room temperature for 3 hours,quenched with water (20 mL) and extracted with ethyl acetate (20 mL).The organic layer was washed with water (2×20 mL) and brine (20 mL),dried over anhydrous sodium sulfate, filtered and concentrated in vacuoto yield the first intermediate compound (1.91 g, 92%) as a yellow oil.MS: ES+ 343.20 (M+1)⁺.

A second intermediate compound,1-(7-Methoxy-naphthalen-1-yl)-piperazine, was produced as follows:4-(7-Methoxy-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester (1.70 g, 4.97 mmol) was dissolved in dichloromethane (10 mL) andtrifluoroacetic acid (2 mL). The mixture was stirred at room temperaturefor 24 hours and then diluted with hexanes (50 mL). The solids werecollected by vacuum filtration and rinsed with hexanes (2×30 mL) toyield the second intermediate compound (2.18 g, quant.) as a purplepowder. ¹H NMR (400 MHz, dmso-d₆) δ 8.90 (s, 2H), 7.80 (d, 1H), 7.60 (d,1H), 7.40 (s, 1H), 7.30 (t, 1H), 7.20-7.10 (m, 2H), 3.95 (s, 3H),3.80-3.40 (m, 8H).

The reductive amination procedure from Example A1 was followed using1-(7-methoxy-naphthalen-1-yl)-piperazine to give the title compound. ¹HNMR (400 MHz, dmso-d₆) δ 10.22 (s, 1H), 7.80 (d, 1H), 7.55-7.42 (m, 2H),7.40 (s, 1H), 7.26 (t, 1H), 7.18 (d, 1H), 7.10 (d, 1H), 6.40 (d, 1H),4.20 (t, 2H), 3.84 (s, 3H), 3.15-2.90 (m, 4H), 2.80-2.55 (m, 6H),2.44-2.40 (m, 4H), 1.80-1.50 (m, 4H), MS ES+ 461.22 (M+1)⁺.

Example A74 Synthesis of7-{4-[4-(7-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, Trifluoro-methanesulfonic acid7-chloro-3,4-dihydro-naphthalen-1-yl ester, was produced as follows: Toa stirred solution of 7-chloro-1-tetralone (6 g, 33.33 mmol) in dry THF(140 mL) at −78° C. was added 1 M solution of lithiumbis(trimethylsilyl) amide in THF (40 mL, 40 mmol) over 5 min under N₂.The reaction mixture was stirred for 1 h andN-phenyltrifluoromethanesulfonimide (14.44 g, 40 mmol) was added in oneportion. The reaction mixture was allowed to warm to room temperatureand stirred for 2 h. The solvent was removed in vaccuo and the residuewas dissolved in EtOAc (200 mL), and washed successively with 2M NaOH,H₂O and brine. Drying over Na₂SO₄ and evaporation under vaccuo yielded abrown oil. Purification by chromatography on silica gel (10%EtOAc:hexanes) gave the first intermediate compound as an oil (9.78 g,95%). ¹H-NMR (400 MHz, CDCl₃) δ 7.32 (d, 1H), 7.24 (dd, 1H), 7.12 (d,1H), 6.06 (t, 1H), 2.84 (t, 2H), 2.53 (m, 2H).

A second intermediate compound, Trifluoro-methanesulfonic acid7-chloro-naphthalen-1-yl ester, was produced as follows: To a stirredsolution of trifluoro-methanesulfonic acid7-chloro-3,4-dihydro-naphthalen-1-yl ester (9.0 g, 28.8 mmol) in dioxane(150 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (13.0 g,57.7 mmol). The reaction mixture was refluxed for 24 h, and the solventwas removed under vaccuo. EtOAc (250 mL) was added, the mixture waswashed with H₂O and brine, and dried over Na₂SO₄. Evaporation undervaccuo and column chromatography of the resulting dark brown oil onsilica gel, eluting with hexanes, yielded the second intermediatecompound as an oil (6.2 g, 55%). ¹H-NMR (400 MHz, CDCl₃) δ 8.04 (d, 1H),7.83 (m, 2H), 7.58-7.48 (m, 3H).

A third intermediate compound,4-(7-Chloro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester, was produced as follows: To an oven dried flask was added1-boc-piperazine (3.48 g, 19.34 mmol), K₃PO₄ (4.78 g, 22.56 mmol),Pd(OAc)₂ (0.361 g, 1.61 mmol), 2-(di-tert-butylphosphino) binaphthyl(0.64 g, 1.61 mmol), THF (40 mL) and trifluoro-methanesulfonic acid7-chloro-naphthalen-1-yl ester (5 g, 16.12 mmol). While stirring thereaction mixture at room temperature, the air in the flask was removedand refilled with N₂. This process was repeated three times. Thereaction was heated at 80° C. for 16 h. Diethyl ether was added at roomtemperature and the mixture was filtered through a pad of silica gel.The brown oil was chromatographed on silica gel eluting withhexanes:chloroform (1:1) and then changing to chloroform (100%) to yieldthe third intermediate compound (3.65 g, 63%) as a brown oil. ¹H-NMR(400 MHz, DMSO-d₆) δ 8.16 (d, 1H), 7.96 (d, 1H), 7.68 (d, 1H), 7.55 (d,1H), 7.52 (t, 1H), 7.21 (d, 1H), 3.61 (s, 4H), 2.98 (s, 4H), 1.42 (s,9H).

A fourth intermediate compound, 1-(7-Chloro-naphthalen-1-yl)-piperazine,was produced as follows: To a solution of4-(7-chloro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester (2.4 g, 6.89 mmol) in CH₂Cl₂ (20 mL) at 0° C. was added dropwisetrifluoroacetic acid (5.24 mL, 68.96 mmol). The reaction mixture wasstirred at room temperature for 2 h and the solvent was evaporated.Addition of Et₂O gave the fourth intermediate compound as a whiteamorphous TFA salt (1.8 g, 73%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.82 (s,2H), 8.19 (d, 1H), 7.98 (d, 1H), 7.73 (d, 1H), 7.57 (m, 2H), 7.24 (d,1H), 3.54-3.11 (m,8H).

The reductive amination procedure from Example A1 was followed using1-(7-chloro-naphthalen-1-yl)-piperazine to give the title compound.¹H-NMR (400 MHz, DMSO-d₆) δ 10.28 (s, 2H), 8.12 (d, 1H), 7.98 (d, 1H),7.74 (d, 1H), 7.58-7.49 (m, 3H), 7.28 (d, 1H), 6.38 (d, 1H), 4.24 (t,2H), 3.64 (m, 2H), 3.50-3.14 (m, 8H), 2.78 (t, 2H), 2.48 (m, 2H),1.96-1.75 (m, 4H).

Example A75 Synthesis of7-{4-[4-(5-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, 5-Chloro-naphthalen-1-ol, was produced asfollows: To a cold solution of 5-amino-naphthalen-1-ol in conc. HCl (100mL) and H₂O (100 mL) at 0° C. was added dropwise a solution of NaNO₂(12.36 g, 190 mmol) in H₂O (20 mL). Freshly prepared CuCl (17.75 g, 190mmol) was dissolved in conc. HCl (20 ml) and added to the reactionmixture. The reaction mixture became very thick and black foamy materialresided on the top of the reaction mixture. CH₃CN (50 ml) was added tomake the reaction mixture homogenous. The reaction was brought to roomtemperature and stirred at 65° C. for 20 min. Ethyl acetate (500 mL) wasadded and the organic layer was separated and washed with H₂O (3×100mL), brine, dried over Na₂SO₄ and evaporated under vaccuo. The darkblack material was chromatographed on a silica column, eluting withCHCl₃ and then changing to CHCl₃:MeOH (98:2), to yield compound thefirst intermediate compound as an oil (4.16 g, 19%). ¹H-NMR (400 MHz,CDCl₃) δ 8.18 (d, 1H), 7.82 (d, 1H), 7.59 (d, 1H), 7.42-7.37 (m, 2H),6.86 (d, 1H), 5.96 (s, 1H).

A second intermediate compound, Trifluoro-methanesulfonic acid5-chloro-naphthalen-1-yl ester, was produced as follows: To a coldsolution of 5-chloro-naphthalen-1-ol (3.7 g, 20.78 mmol) in CH₂Cl₂ (50mL) at 0° C. was added dropwise Et₃N (5.78 mL, 41.6 mmol), followed bytrifluoromethanesulfonic anhydride (5.24 mL, 31.2 mmol). The reactionmixture was stirred at 0-5 ° C. for 30 min and saturated NaHCO₃ (50 mL)was added. The organic layer was separated and washed with saturatedNH₄Cl solution, brine and dried over Na₂SO₄. Evaporation under vaccuoand purification by chromatography on silica (3:1 Et₂O/hexanes) yieldedthe second intermediate compound as a colorless oil (5.5 g, 85%). ¹H-NMR(400 MHz, CDCl₃) δ 8.38 (d, 1H), 8.02 (d, 1H), 7.71 (d, 1H), 7.60 (m,2H), 7.58 (d, 1H).

A third intermediate compound,4-(5-Chloro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester, was produced as follows: To an oven dried flask, 1-boc-piperazine(2.95 g, 15.87 mmol), K₃PO₄ (3.92 g, 18.5 mmol), Pd(OAc)₂ (0.296 g, 1.32mmol), 2-(Di-tert-butylphosphino) binaphthyl (0.525 g, 1.32 mmol), THF(40 mL) and trifluoro-methanesulfonic acid 5-chloro-naphthalen-1-ylester (4.1 g, 13.22 mmol) were added. While stirring the reactionmixture at room temperature, the air in the flask was removed andrefilled with N₂. This process was repeated three times. The reactiontemperature was brought to 80° C. and stirred for 18 h. Diethyl etherwas added at room temperature and the mixture was filtered through a padof silica gel. The brown oily material was purified by chromatography onsilica column eluting with hexanes:chloroform (1:1) and then changing tochloroform (100%) to yield the third intermediate compound (1.75 g, 41%)as a brown oil. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.18 (d, 1H), 7.90 (d, 1H),7.68 (d, 1H), 7.58 (t, 1H), 7.53 (t, 1H), 7.22 (d, 1H), 3.61 (s, 4H),2.97 (s, 4H), 1.42 (s, 9H).

A fourth intermediate compound, 1-(5-Chloro-naphthalen-1-yl)-piperazine,was produced as follows: To a solution of4-(5-chloro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester (1.85 g, 5.35 mmol) in CH₂Cl₂ (10 ml) at 0° C. was added dropwisetrifluoromethanesulfonic acid (4.1 ml, 53.5 mmol).The reaction mixturewas stirred at room temperature for 2 h and the solvent was evaporatedunder vaccuo. Addition of Et₂O gave the fourth intermediate compound asa white amorphous solid (1.5 g, 80%). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.84(s, 2H), 8.19 (d, 1H), 7.97 (d, 1H), 7.74 (d, 1H), 7.64 (t, 1H), 7.54(t, 1H), 7.34 (d, 1H), 3.54-3.11 (m, 8H).

The reductive amination procedure from Example A1 was followed using1-(5-chloro-naphthalen-1-yl)-piperazine to give the title compound.¹H-NMR (400 MHz, DMSO-d₆) δ 10.76 (s, 1H), 10.29 (s, 1H), 8.21 (d, 1H),7.98 (d, 1H), 7.74 (d, 1H), 7.68 (t, 1H), 7.54 (m, 2H), 7.36 (d, 1H),6.37 (d, 1H), 4.24 (t, 2H), 3.63 (m, 2H), 3.52-3.13 (m, 10H), 2.78 (t,2H), 1.98-1.68 (m, 4H).

Example A767-{4-[4-(6-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound, 1-(6-Chloro-naphthalen-1-yl)-piperazine, wasproduced as follows: The intermediate compound was prepared from6-amino-naphthalen-1-ol according to the route described in Example A75above. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.91 (s, 2H), 8.18 (d, 1H), 8.03 (d,1H), 7.66 (d, 1H), 7.52 (m, 2H), 7.22 (d, 1H), 3.41 (s, 4H), 3.21 (s,4H).

The reductive amination procedure from Example A1 was followed using1-(6-chloro-naphthalen-1-yl)-piperazine to give the title compound (0.50g, 60%), mp. 215-216° C. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.66 (s, 1H),10.22 (s, 1H), 8.18 (d, 1H), 8.03 (d, 1H), 7.64 (d, 1H), 7.58 (m, 3H),7.22 (d, 1H), 6.38 (d, 1H), 4.22 (t, 2H), 3.62 (m, 2H), 3.51-3.09 (m,1OH), 2.78 (t, 2H), 1.98-1.72 (m, 4H).

Example A777-{4-[4-(8-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, 8-Bromo-naphthalen-1-ylamine, wasproduced as follows: Sodium azide (7.81 g, 120 mmol) was addedportionwise to a suspension of 8-bromo-naphthalene-1-carboxylic acid (5g, 19.92 mmol) in conc. H₂SO₄ (17.5 mL) and CHCl₃ (17.5 mL) at 45° C.The reaction mixture was stirred for 1.5 h and water (150 mL) was addedat room temperature. The mixture was made alkaline with ammoniumhydroxide and extracted with CHCl₃. The organic layer was dried overNa₂SO₄ and evaporated to give the first intermediate compound as a brownoil (4.48 g, 99%). ¹H-NMR (400 MHz, CDCl₃) δ 7.68 (dd, 1H), 7.62 (dd,1H), 7.24 (m, 2H), 7.13 (t, 1H), 6.74 (q, 1H), 5.20 (s, 2H).

A second intermediate compound, 1-Bromo-8-chloro-naphthalene, wasproduced as follows: To a cold solution of 8-bromo-naphthalen-1-ylamine(4.48 g, 20 mmol) in conc. HCl (30 mL) and H₂O (25 mL) at 0° C. wasadded dropwise a solution of NaNO₂ (3.45 g, 50 mmol) in H₂O (10 mL).Freshly prepared CuCl (13.86 g, 140 mmol) was dissolved in conc. HCl (15ml) and was added to the reaction mixture. The reaction was brought toroom temperature and stirred at 65° C. for 30 min. Ethyl acetate (250mL) was added and the organic layer was separated and washed with H₂O(3×100 mL), brine, dried over Na₂SO₄ and evaporated under vaccuo. Thedark black material was purified by chromatography on silica, elutingwith CHCl₃ and then changing to CHCl₃:MeOH (98:2), to yield the secondintermediate compound as an oil (2.95 g, 72%). ¹H NMR (400 MHz, CDCl₃) δ7.92 (dd, 1H), 7.82-7.75 (m, 2H), 7.65 (dd, 1H), 7.36 (t, 1H), 7.26 (q,1H).

A third intermediate compound, 1-(8-Chloro-naphthalen-1-yl)-piperazine,was produced as follows: To an oven dried flask, 1-boc-piperazine (1.2g, 6.47 mmol), NaOtBu (0.724 g, 7.54 mmol), Pd(OAc)₂ (0.12 g, 0.539mmol), 2-(di-cyclohexylphosphino) biphenyl (0.12 g, 0.539 mmol), toluene(15 mL) and 1-bromo-8-chloro-naphthalene (1.3 g, 5.39 mmol) were added.While stirring the reaction mixture at room temperature, the air in theflask was removed and refilled with N₂. This process was repeated threetimes. The reaction mixture was stirred for 3 h at 80-90° C. Diethylether was added at room temperature and the mixture was filtered througha pad of silica gel. The brown oily material was purified bychromatography on silica, eluting with hexanes:chloroform (1:1) and thenchanging to 100% chloroform, to give4-(8-chloro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester as an oil (1.35 g, 72%). ¹H-NMR (400 MHz, CDCl₃) δ 7.73 (dd, 1H),7.56 (dd, 1H), 7.52 (dd, 1H), 7.42 (t, 1H), 7.34 (t, 1H), 7.18 (dd, 1H),4.16 (s, 2H), 3.38 (s, 2H), 3.22 (m, 2H), 2.76 (m, 2H), 1.45 (s, 9H).

To a solution of 4-(8-chloro-naphthalen-1-yl)-piperazine-1-carboxylicacid tert-butyl ester (1.34 g, 3.87 mmol) in CH₂Cl₂ (10 mL) at 0° C. wasadded dropwise trifluoroacetic acid (2.94 mL, 38.7 mmol). The reactionmixture was stirred at room temperature for 1.5 h and the solvent wasevaporated under vaccuo. Addition of Et₂O gave the third intermediatecompound as a white amorphous solid (1.03 g, 74%). ¹H-NMR (400 MHz,DMSO-d₆) δ 8.92 (s, 1H), 8.71 (s, 1H), 7.92 (dd, 1H), 7.76 (d, 1H), 7.62(dd, 1H), 7.54 (t, 1H), 7.46 (m, 1H), 7.33 (dd, 1H), 3.44-3.27 (m, 4H),3.20-2.91 (m, 4H).

The reductive amination procedure from Example A1 was followed using1-(8-chloro-naphthalen-1-yl)-piperazine to give the title compound(0.303 g, 48%). ¹H-NMR (400 MHz, DMSO-d₆) δ 10.31 (s, 1H), 10.21 (s,1H), 7.94 (dd, 1H), 7.76 (d, 1H), 7.62 (dd, 1H), 7.54 (m, 2H), 7.46 (t,1H), 7.32 (d, 1H), 6.38 (d, 1H), 4.22 (t, 2H), 3.62 (m, 2H), 3.44-3.22(m, 8H), 3.08 (m, 2H), 2.79 (m, 2H), 1.92-1.72 (m, 4H).

Example A787-{4-[4-(7-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,4-(7-Trifluoromethanesulfonyloxy-naphthalen-1-yl)-piperazine-1-carboxylicacid tert-butyl ester, was produced as follows:4-(7-Hydroxy-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester (2.00 g, 6.09 mmol) was dissolved in dichloromethane (30 mL) andtriethylamine (1.23 g, 1.70 mL, 12.2 mmol) were added. The mixture wascooled to 0° C. and trifluoromethanesulfonic anhydride (2.58 g, 1.54 mL,9.15 mmol) was added dropwise. The mixture was stirred at 0° C. for 30minutes and water (20 mL) was added. The organic layer was washed withsaturated sodium bicarbonate (20 mL) and brine (20 mL), dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo. Thecrude oil was purified by column chromatography (5:1, hexanes/ethylacetate) to yield the first intermediate compound (2.50 g, 89%) as anorange oil that solidified. ¹H NMR (400 MHz, dmso-d₆) δ 8.20-8.10 (m,2H), 7.78 (d, 1H), 7.65-7.50 (m, 2H), 7.30 (d, 1H), 3.80-3.40 (m, 4H),3.05-2.90 (m, 4H), 1.40 (s, 9H).

A second compound, 1-(8-Piperazin-1-yl-naphthalen-2-yl)-ethanone, wasproduced as follows:4-(7-Trifluoromethanesulfonyloxy-naphthalen-1-yl)-piperazine-1-carboxylicacid tert-butyl ester (2.50 g, 5.44 mmol) was dissolved indimethylformamide (15 mL) and the solution was degassed for 30 minutes.Triethylamine (1.10 g, 1.52 mL, 10.87 mmol), butyl vinyl ether (2.72 g,3.50 mL, 27.17 mmol), palladium acetate (61 mg, 0.27 mmol), and1,3-bis(diphenylphosphino)-propane (112 mg, 0.27 mmol) were addedsequentially and the mixture was heated to 80° C. and stirred for 3hours at this temperature, then the temperature was lowered to 40° C.and stirred for an additional 15 hours, then cooled to room temperature.The mixture was extracted with dichloromethane (30 mL), and the organiclayer was washed with water (3×30 mL) and brine (30 mL), dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo. Thecrude oil was filtered through a short plug of silica gel, eluting with3:1 hexanes/ethyl acetate to yield a mixture of4-[7-(1-butoxy-vinyl)-naphthalen-1-yl]-piperazine-1-carboxylic acidtert-butyl ester and4-(7-acetyl-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester (2.14 g).

This mixture (2.14 g) was dissolved in a mixture of dichloromethane (4mL), trifluoroacetic acid (3 mL) and water (1 mL) and stirred at roomtemperature for 4 hours. The mixture was evaporated in vacuo and hexanes(30 mL) were added. The precipitate was filtered off and washed withhexanes (20 mL) to yield the second intermediate compound (2.1 g,quant.) as an orange solid. ¹H NMR (400 MHz, dmso-d6) δ 8.95 (s, 1H),8.70 (s, 1H), 8.05-7.98 (m, 2H), 7.76 (d, 1H), 7.60 (t, 1H), 7.30 (d,1H), 3.50-3.30 (m, 4H), 3.30-3.10 (m, 4H), 2.75 (s, 3H).

The reductive amination procedure from Example A1 was followed using1-(8-piperazin-1-yl-naphthalen-2-yl)-ethanone to give the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 8.85 (s, 1H), 8.00 (d, 1H), 7.85 (d,1H), 7.60-7.50 (m, 3H), 7.38 (d, 1H), 7.18 (d, 1H), 4.24 (t, 2H),3.25-3.10 (m, 4H), 2.86 (t, 2H), 2.85-2.76 (m, 4H), 2.75 (s, 3H), 2.64(t, 2H), 2.55 (t, 2H), 1.90-1.70 (m, 4H), MS ES+473.24 (M+H)⁺.

Example A79 Synthesis of7-{4-[4-(6-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound, 1-(5-Piperazin-1-yl-naphthalen-2-yl)-ethanone,was produced as follows: The intermediate compound was prepared from4-(6-hydroxy-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester according to the route described in Example A78. ¹H NMR (400 MHz,dmso-d₆) δ 8.90 (s, 1H), 8.65 (s, 1H), 8.20 (d, 1H), 7.98 (d, 1H), 7.86(d, 1H), 7.60 (t, 1H), 7.36 (d, 1H), 3.60-3.18 (m, 8H), 2.70 (s, 3H).

The reductive amination procedure from Example A1 was followed using1-(5-piperazin-1-yl-naphthalen-2-yl)-ethanone to give the title compound(366 mg, 83%). ¹H NMR (400 MHz, dmso-d₆) δ 10.30 (s, 1H), 8.70 (s, 1H),8.20 (d, 1H), 7.99 (d, 1H), 7.88 (d, 1H), 7.60 (t, 1H), 7.54 (d, 1H),7.36 (d, 1H), 6.40 (d, 1H), 4.20 (t, 2H), 3.80-3.60 (m, 6H), 3.40 (t,2H), 3.30-3.10 (m, 4H), 2.80 (t, 2H), 2.70 (s, 3H), 1.96-1.70 (m, 4H),MS ES+ 473.19 (M+H)⁺ (Exact mass: 472.25).

Example A80 Synthesis of7-{4-[4-(5-Acetyl-naphthalen-1-yl)-pirerazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound, 1-(5-Piperazin-1-yl-naphthalen-1-yl)-ethanone,was produced as follows: The intermediate compound was prepared from4-(5-hydroxy-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester according to the route described in Example A78. 1H-NMR (400 MHz,CDCl3): 8.80 (br s, 2H), 8.42 (d, J=7.7 Hz, 1H), 8.35 (d, J=7.8 Hz, 1H),8.12 (d, J =7.0 Hz, 1H), 7.65 (m, 1H), 7.57 (m, 1H), 7.25 (d, J=6.8 Hz,1H), 3.60 -3.10 (m, 8H).

The reductive amination procedure from Example A1 was followed using1-(5-piperazin-1-yl-naphthalen-1-yl)-ethanone to give the title compound(0.41 g, 76%). ¹H-NMR (400 MHz, CDCl₃): 10.05 (s, 1H), 8.40 (d, J=7.8Hz, 1H), 8.30 (d, J=7.5 Hz, 1H), 8.13 (d, J=6.6 Hz, 1H), 7.70-7.50 (m,3H), 7.30 (d, J=6.5 Hz, 1H), 6.40 (d, J=7.9 Hz, 1H), 4.30 (t, J=3.2 Hz,2H), 3.70 (m, 2H), 3.60 -3.20 (m, 8H), 2.80 (t, J=8 Hz, 2H), 2.70 (s,3H), 2.50 (m, 2H), 2.00-1.80 (m, 4H).

Example A81 Synthesis of7-{4-[4-(4-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound, 1-(4-Piperazin-1-yl-naphthalen-1-yl)-ethanone,was produced as follows: The intermediate compound was prepared from4-(4-bromo-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester according to the route described in Example A78. ¹H-NMR (400 MHz,DMSO-d₆): δ 8.90 (s, 2H), 8.80 (d, 1H), 8.20 (d, 1H), 8.10 (d, 1H), 7.60(m, 2H), 7.20 (d, 1H), 3.45 (s, 4H), 3.25 (s, 4H), 2.65 (s, 3H).

The reductive amination procedure from Example A1 was followed using1-(4-piperazin-1-yl-naphthalen-1-yl)-ethanone to give the title compound(0.40 g, 80%). ¹H-NMR (400 MHz, DMSO-d₆): δ: 10.40 (s, 1H), 10.25 (s,1H), 8.80 (d, 1H), 8.20 (m, 2H), 7.60 (m, 2H), 7.50 (d, 1H), 7.20 (d,1H), 6.40 (d, 1H), 4.23 (m, 2H), 3.80-3.20, 10H), 2.80 (m, 2H), 2.70 (s,3H), 2.50 (m, 2H), 2.00-1.75 (m, 4H).

Example A82 Synthesis of7-{4-[4-(2-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound, 1-(1-Piperazin-1-yl-naphthalen-2-yl)-ethanone,was produced as follows: The intermediate compound was prepared from4-(2-hydroxy-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butylester according to the route described in Example A78. ¹H-NMR (400 MHz,DMSO-d₆): δ: 8.35 (m, 1H), 8.00 (m, 1H), 7.80 (m, 1H), 7.60 (m, 3H),3.40-3.20 (m, 8H), 2.70 (s, 3H).

The reductive amination procedure from Example A1 was followed using1-(1-piperazin-1-yl-naphthalen-2-yl)-ethanone to give the titlecompound. ¹H-NMR (400 MHz, DMSO-d₆): δ: 12.90 (s, 1H), 8.30 (s, 1H),7.90 (m, 2H), 7.80 (m, 1H), 7.70-7.50 (m, 3H), 7.45 (m, 2H), 6.40 (d,J=6.5 Hz, 1H), 4.40-4.10 (m, 4H), 3.70 (m, 2H), 3.40-3.00 (m, 6H), 2.90(m, 2H), 2.67 (m, 5H), 2.40-1.90 (m,4H).

Example A83 Synthesis of8-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyl]-piperazin-1-yl}-naphthalene-2-carbonitrile

A first intermediate compound, (7-Cyano-naphthalen-1-yl)-carbamic acidbenzyl ester, was produced as follows:Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (0.24 g, 0.23mmol), 1,1′-bis(diphenylphosphino)-ferrocene (1.04 g, 1.87 mmol), KCN(3.05 g, 47.0 mmol), trifluoro-methanesulfonic acid8-benzyloxycarbonylamino-naphthalen-2-yl ester (10 g, 23.52 mmol), andNMP (20 mL) were combined sequentially and stirred at room temperaturefor 20 minutes until a yellow reaction complex was formed. The reactionmixture was stirred for 1 h at 80° C. and then cooled to roomtemperature. The dark brown reaction mixture was purified bychromatography on silica, eluting with hexanes:EtOAc (8.5:1.5) and thenchanging to hexanes:EtOAc (8:2), to give the first intermediate compound(5.81 g, 82%) as a brown oil which solidified upon standing at roomtemperature. ¹H-NMR (400 MHz, CDCl₃) δ 8.34 (s, 1H), 7.93 (d, 2H), 7.70(d, 1H), 7.62 (m, 2H), 7.46-7.32 (m, 5H), 5.24 (s, 2H).

A second intermediate compound, 8-Amino-naphthalene-2-carbonitrile, wasproduced as follows: To (7-cyano-naphthalen-1-yl)-carbamic acid benzylester (5.81 g, 19.23 mmol) was added 33% HBr in HOAc (35 mL) and themixture was stirred at room temperature for 6 h. Et₂O was added and theproduct was crystallized as a yellow solid. The solid was washed threetimes with Et₂O to give the second intermediate compound (4.22 g, 88%)as yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.16 (d, 1H),7.86 (m, 2H), 7.69 (t, 1H), 7.49 (d, 1H).

A third intermediate compound,8-Piperazin-1-yl-naphthalene-2-carbonitrile, was produced as follows: Amixture of 8-amino-naphthalene-2-carbonitrile (1 g, 4.03 mmol),bis-(2-chloroethyl)amine hydrochloride (0.778 g, 4.4 mmol), Nal (0.299g, 2.01 mmol), and 1-hexanol (1 mL) in chlorobenzene was heated at 140°C. for 20 h. The reaction mixture was concentrated and the residue wasstirred with Et₂O:hexanes (1:1) and the solvent was decanted. The brownmaterial was purified by chromatography on silica, eluting withMeOH:CHCl₃ (3:97) and then changed to MeOH:CHCl₃:NH₃ (10:89:1), to yieldthe third intermediate compound (0.75 g, 79%) as a light yellow oil.¹H-NMR (400 MHz, CDCl₃) δ 8.79 (s, 1H), 8.64 (s, 1H), 8.13 (d, 1H), 7.80(m, 2H), 7.64 (t, 1H), 7.37 (d, 1H), 3.62 (m, 2H), 3.42 (m, 2H),3.12-3.05 (m, 4H).

The reductive amination procedure from Example A1 was followed using8-piperazin-1-yl-naphthalene-2-carbonitrile to give the title compound(0.245 g, 37%). ¹H-NMR (400 MHz, DMSO-d₆) δ 10.21 (s, 1H), 8.64 (s, 1H),8.14 (d, 1H), 7.82 (m, 2H), 7.69 (t, 1H), 7.52 (d, 1H), 7.36 (d, 1H),6.38 (d, 1H), 4.22 (t, 2H), 3.82-3.15 (m, 12H), 2.79 (m, 2H), 1.96-1.76(m, 4H).

Example A84 Synthesis ofN-(8-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yioxy)-butyl]-piperazin-1-yl}-naphthalen-2-yl)-acetamide

The reductive amination procedure from Example A1 was followed usingN-(8-piperazin-1-yl-naphthalen-2-yl)-acetamide to give the titlecompound. MS: APCl: M+1: 488.2 (Exact Mass: 487.26).

Example A85 Synthesis of7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,7-(4-benzyloxybutoxy)-[1,8]naphthyridin-2-one, was produced according tothe reaction summarized below, as follows.7-Fluoro-1H-[1,8]naphthyridin-2-one (210 g, 1.28 moles),tetrabutylammonium bromide (20 g, 0.064 mole), 4-benzyloxybutanol (235.8mL, 1.34 mole), and THF (2.5 L) were charged to a 12 L three-neck roundbottom flask equipped with a mechanical stirrer, an addition funnel, andinerted with nitrogen (g). The suspension was stirred at 25° C. for 30minutes. An ice bath was used to cool the reaction mixture and 1 Mpotassium tert-butoxide in THF (2.87 L, 2.87 mole) was added viaaddition funnel at a rate to keep the internal temperature below 30° C.Upon complete addition, the thick slurry became a solution and wasstirred at 25° C. for 4 hours or until the reaction was complete byLC/MS analysis. 1N HCl (1.6 L, 1.6 mole) was added slowly to keep thereaction temperature below 30° C. and stirred for 30 minutes. THF wasremoved using a rotoevaporator and 7 L of ethyl acetate was added toform a biphasic mixture. The mixture was transferred to a separatoryfunnel, where the aqueous layer was collected and reextracted with 1 Lof ethyl acetate. The ethyl acetate layers were combined, filteredthrough Celite, washed with water, then with brine, and collected. MgSO₄was added, then filtered, and product was concentrated under vacuum to ayellow solid (405 g, 1.25 mole, 97.8%). MS: APCl: M+1: 325.1 (ExactMass: 324.15). ¹HNMR (CDCl₃).

A second intermediate compound,7-(4-Hydroxybutoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was producedaccording to the reaction summarized below, as follows. The firstintermediate compound, 7-(4-Benzyloxybutoxy)-1H-[1,8]naphthyridin-2-one(132.4 g, 0.408 mole), and MeOH (1.3 L) were charged to a pressurereactor with 20% Palladium on Carbon (20.0 g, 50% water-wet) andhydrogenated for 48 hours at 45° C. and 50 psi. The reaction wasmonitored by mass spectroscopy or HPLC. Upon completion, the palladiumcatalyst was filtered and the filtrate was concentrated to an off-whitesolid. Yield=96.3 g, Quantitative. MS: APCl: M+1: 237.1. ¹HNMR (CDCl₃).

A third intermediate compound,7-(4-chlorobutoxy)-3,4-dihydro-1H[1,8]naphthyridin-2-one, was producedaccording to the reaction summarized below, as follows. The secondintermediate compound,7-(4-Hydroxybutoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (121 g, 0.515mole), was stirred with THF (1.2 L) in a 3 L round-bottom flask equippedwith an addition funnel, thermocouple, and inerted with nitrogen.Methane sulfonyl chloride (48 mL, 0.618 mole) was added and the reactionwas cooled to −11° C. with an acetone/ice bath. Triethylamine (100 mL,0.721 mole) was added via addition funnel at a rate to keep the internaltemperature below 0° C. Following complete addition, the reaction waswarmed to ambient temperature. TLC (50% CH₂Cl₂-Ethyl Acetate) showed thereaction was complete. LiCl (43.6 g, 1.03 mole) was added to thereaction suspension and refluxed for 12 hours. TLC showed the reactionwas complete. THF was removed via vacuum distillation and Ethyl Acetate(1.2 L) was added. The organic layer was washed with water (500 mL),sat. NaHCO₃ (500 mL), and brine. MgSO₄ was used to dry the organicsolution, which was filtered, concentrated, and dried to a solid thatstuck tightly to the walls of the flask. Yield=120 g, 92%. MS: APCl:M+1: 255.0. ¹HNMR (CDCl₃).

Finally,7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)butoxy]-3,4-dihydro-1H[1,8]naphthyridin-2-onewas produced according to the following reaction, as described below.The third intermediate compound,7-(4-Chlorobutoxy)-3,4-dihydro-1H[1,8]naphthyridin-2-one (119 g, 0.469mole), 1-naphthalen-1-yl-piperazine hydrochloride (110.7 g, 0.446 mole),and potassium carbonate (185 g, 1.339 mole) were charged to a 2 L roundbottomed flask equipped with mechanical stirring and a condenser. Water(1.2 L) was added and the reaction was refluxed for 12 hours undernitrogen gas. The reaction was cooled to ambient temperature and thewater was decanted, leaving a clump of tan solids. Ethyl acetate (1.2 L)was added, along with water (500 mL), and the solids were stirred for 30minutes to form a bi-layer. Water (500 mL) was added to the ethylacetate layer for another wash, followed by a wash with brine (500 mL).MgSO₄ was added to the ethyl acetate, which was then filtered andconcentrated to a brown solid. Yield=164 g, 85%. MS: APCl: M+1: 431.2.¹HNMR (CDCl₃).

The resulting product was recrystallized from acetitrile (7 mL/g) byheating the acetonitrile slurry to 60° C., where a solution developed.The solution was then cooled at a rate of −3° C./hr to get to ambienttemperature. The recrystallized slurry was then cooled to 0° C. with anice-bath, filtered cold, and dried to give the purified material ingreater than 97% HPLC purity (294 nm). Recrystallization yield=80-85%.

Example B1 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

A first intermediate compound,2-Benzyloxy-7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-[1,8]naphthyridine,was produced as follows: To a solution of4-(tetrahydro-pyran-2-yloxy)-1-butanol (3.27 9, 18.8 mmol, 1.2 equiv) inTHF (20 mL) cooled to ⁰° C. was added KO^(t)Bu (1M in THF, 18 mL, 18mmol, 1.15 equiv). The solution was stirred at 0° C. for 20 min and thenadded via cannula to a suspension of2-benzyloxy-7-chloro-[1,8]naphthyridine (4.24 g, 15.66 mmol) in THF (50mL) cooled to 0° C. The reaction turned orange and became homogenous.After 30 min at 0° C., saturated NH₄Cl and H₂O were added to quench thereaction. The mixture was extracted with EtOAc. The organic layer waswashed with saturated NaHCO₃, H₂O and brine, dried over Na₂SO₄ andconcentrated. The crude was absorbed onto SiO₂ and purified by liquidchromatography (20-30% EtOAc/Hexanes) to give the first intermediatecompound as a pale yellow oil (3.71 g, 9.08 mmol, 58%). MS: APCl: M+1:409.2 (Exact Mass: 408.20).

A third intermediate compound,7-(4-Hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one, was produced asfollows:2-Benzyloxy-7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-[1,8]naphthyridine(620 mg, 1.52 mmol) was hydrogenated using 5% Pd/C in MeOH for 40 min.The reaction was filtered and concentrated. The residue was dissolved inEtOH (5 mL) and PPTS (25 mg, 0.10 mmol) was added. The mixture washeated at 60° C. overnight. The reaction was concentrated and purifiedby liquid chromatography (6% MeOH/CH₂Cl₂) to give the third intermediatecompound as a white solid (282 mg, 1.20 mmol, 79%). MS: APCl: M+1: 235.1(Exact Mass: 234.10).

This intermediate was also prepared using the following procedure:

To a suspension of 60% NaH (83.6 g, 2.09 mol) in NMP (1 L) was added dry1,4-butanediol (300 mL, 3.39 mol, concentrated from toluene) dropwise tocontrol foaming. The reaction temperature increased to 50° C. and themixture was stirred at 60° C. for 15 min.7-Chloro-1H-[1,8]naphthyridin-2-one (146 9, 0.813 mol) was added withstirring and the reaction was heated at 68° C. for 20 h. CH₃CN (5 L) wasadded and the mixture was filtered and the filter cake was washed withCH₃CN (500 mL) and THF (500 mL). The filter cake was reslurried with THF(3 L) and 3N HCl in MeOH (290 mL, 0.870 mol) was added. The mixture washeated at 60° C. for 1 h and then filtered through celite washing withTHF (1 L). The filtrate was concentrated to a volume of 500 mL and THF(1.5 L), Darco (10 9) and magnesol (100 mL) was added. The mixture wasstirred at 40° C. for 30 min and then filtered washing with THF (500mL). The filtrate was concentrated to 500 mL, CH₃CN was added and themixture was concentrated to 1 L. The resulting solid was filtered,washed with CH₃CN (200 mL) and Et₂O (300 mL) and dried at 50° C. toyield the title compound (101 g, 53%). The filtrate upon standing gaveadditional crystals, which were collected by filtration, washed anddried as before to give additional title compound (17 g, total yield of62%).

A fourth intermediate compound,4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde, wasproduced as follows: Using Swern oxidation: To a solution of oxalylchloride (0.12 mL, 1.32 mmol, 1.1 equiv) in CH₂Cl₂ (2.5 mL) cooled to−78° C. was added DMSO (0.18 mL, 2.6 mmol). The reaction was stirred for5 min and then 7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one (282 mg,1.20 mmol) was added as a solution in CH₂Cl₂ (4.5 mL) and DMSO (1.2 mL)via cannula over 5 min. The DMSO was necessary to dissolve the alcohol.The reaction was stirred for 15 min and Et₃N (0.83 mL, 6.0 mmol, 5equiv) was added. The reaction turned cloudy. The reaction was allowedto stir at −78° C. for 10 min and then warmed to RT. After 30 min at RT,H₂O was added and the mixture was extracted with CH₂Cl₂. The organiclayer was washed with brine, dried over MgSO₄ and concentrated to givethe fourth intermediate compound as a light brown oil (340 mg), whichwas used in the next reaction. MS: APCl: M+1: 233.1 (Exact Mass:232.08).

Using IBX oxidation: To a solution of7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one (223 mg, 0.952 mmol) inDMSO (3 mL) was added a solution of IBX (400 mg, 1.43 mmol) in DMSO (4.8mL, 0.3 M). The reaction was stirred at room temperature for 6 h, cooledto 0° C. and quenched with 5% NaHCO3. The mixture was extracted withCH2Cl2 (4×). The organic layer was washed with 5% NaHCO3, dried overMgSO4 and concentrated to give the title compound as a pale yellow solid(175 mg, 0.754 mmol, 79%). MS: APCl: M+1: 233.1 (Exact Mass: 232.08).

To a solution of4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (crudefrom previous reaction) in dichloroethane (6 mL) was added2,3-dichlorophenylpiperazine hydrochloride (321 mg, 1.20 mmol) followedby Et₃N (0.34 mL, 2.40 mmol, 2 equiv). The resulting suspension wasstirred for 5 min and NaBH(OAc)₃ (356 mg, 1.68 mmol, 1.4 equiv) wasadded as a powder. The reaction was stirred at room temperature for 2 h.The reaction was quenched with saturated NaHCO₃ and H₂O and the mixturewas extracted with EtOAc. The organic layer was washed with saturatedNaHCO₃ and brine, dried over Na₂SO₄ and concentrated. Purification byliquid chromatography (4-5% MeOH/CH₂Cl₂) gave the title compound as awhite foam (378 mg, 0.845 mmol, 70% over 2 steps). The foam wasdissolved in Et₂O/CH₂Cl₂ and 1N HCl in Et₂O (0.82 mL) was added. Theresulting white precipitate was collected by filtration, washed withEt₂O and dried to give a white solid (355 mg). MS: APCl: M+1: 447.1(Exact Mass: 446.13).

Example B2 Synthesis of7-{4-[4-(2-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(2-chloro-3-trifluoromethyl-phenyl)-piperazine to give the titlecompound (0.55 g, 60%). ¹H NMR (400 MHz, CDCl₃): δ 9.45 (s, 1H), 7.75(d, 1H), 7.65 (d, 1H), 7.35 (m, 3H), 6.60 (d, 1H), 6.55 (d, 1H), 4.40(t, 2H), 3.15 (br s, 4H), 2.65 (br s, 4H), 2.50 (m, 2H), 1.85 (m, 2H),1.75 (m, 2H). MS ES: m/z 480.93 (M+H)⁺ (Exact mass: 480.15).

Example B3 Synthesis of7-{4-[4-(2-Acetyl-3-chloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

In a manner similar to that of other examples above,1-(2-chloro-6-piperazin-1-yl-phenyl)-ethanone was coupled by reductiveamination to4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followedby typical workup and purification to give the title compound. MS: APCl:M+1: 455.2 (Exact Mass: 454.18).

Example B4 Synthesis of7-{4-[4-(3-Chloro-2-ethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

In a manner similar to that of other examples above,1-(3-chloro-2-ethyl-phenyl)-piperazine hydrochloride was coupled byreductive amination to4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followedby typical workup and purification to give the title compound. MS: APCl:M+1: 441.2 (Exact Mass: 440.20).

Example B5 Synthesis of7-{4-[4-(2-Acetyl-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

In a manner similar to that of other examples above,1-(2-fluoro-6-piperazin-1-yl-phenyl)-ethanone was coupled by reductiveamination to4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followedby typical workup and purification to give the title compound. MS: APCl:M+1: 439.2 (Exact Mass: 438.21).

Example B6 Synthesis of7-{4-[4-(3-Acetyl-2-chloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

In a manner similar to that of other examples above,1-(2-chloro-3-piperazin-1-yl-phenyl)-ethanone trifluoroacetate wascoupled by reductive amination to4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followedby typical workup and purification to give the title compound, mp108-110° C. MS: APCl: M+1: 455.2 (Exact Mass: 454.18).

Example B7 Synthesis of7-{4-[4-(2-Chloro-4-fluoro-5-methyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(2-chloro4-fluoro-5-methyl-phenyl)-piperazine hydrochloride to givethe title compound (0.246 g, 51%). MS: APCl: M+1: 445.2 (Exact mass:444.17).

Example B8 Synthesis of7-{4-[4-(2-Chloro4-fluoro-3-methyl-phenyl-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(2-chloro-4-fluoro-3-methyl-phenyl)-piperazine hydrochloride to givethe title compound (0.223 g, 46%). MS: APCl: M+1: 445.2 (Exact mass:444.17).

Example B9 Synthesis of7-{4-[4-(5-Chloro-2-isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

To a suspension of4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.206 g,0.887 mmol, 1 eq) and 1-(5-chloro-2-isopropoxy-phenyl)-piperazine (0.328g, 0.977 mmol, 1.1 eq) in dichloroethane (5 mL) was added NaBH(OAc)₃(0.535 g, 2.524 mmol, 2.84 eq). The slurry was allowed to stir overnightat room temperature (18 h). Analysis by HPLC showed reaction mostlycomplete. The mixture was diluted with Ethyl Acetate and quenched withsaturated NaHCO₃. The organic phase was washed with brine, dried overNa₂SO₄, filtered and evaporated in vacuo. Purification by silica gelchromatography (2% MeOH/CH₂Cl₂) followed by formation of the HCl saltusing 1N HCl in ether provided the title compound (0.164 g, 39%). MS:APCl: M+1: 471.2 (Exact Mass: 470.21).

Example B10 Synthesis of7-{4-[4-(2-lsopropoxy-phenyl)-piperazin-1-yl]-butoxy-}1H-[1,8]naphthyridin-2-one

The above reductive amination procedure using1-(2-isopropoxy-phenyl)-piperazine afforded the title compound. MS:APCl: M+1: 437.3 (Exact Mass: 436.25).

Example B11 Synthesis of7-{4-[4-(2-Isobutoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The above reductive amination procedure using1-(2-isobutoxy-phenyl)-piperazine afforded the title compound. MS: APCl:M+1: 451.2 (Exact Mass: 450.26).

Example B12 Synthesis of7-[4-(4-o-Tolyl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-o-tolyl-piperazine to give the title compound. MS: APCl: M+1: 393.2(Exact mass: 392.22).

Example B13 Synthesis of7-{4-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(4-fluoro-phenyl)-piperazine to give the title compound. MS: APCl:M+1: 397.1 (Exact mass: 396.20).

Example B14 Synthesis of7-{4-[4-(3-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(3-chloro4-fluoro-phenyl)-piperazine to give the title compound. MS:APCl: M+1: 431.2 (Exact mass: 430.16).

Example B15 Synthesis of7-{4-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(3-trifluoromethyl-phenyl)-piperazine to give the title compound. MS:APCl: M+1: 447.2 (Exact mass: 446.19).

Example B16 Synthesis of7-{4-[4-(2-Trifluoromethyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(2-trifluoromethyl-phenyl)-piperazine to give the title compound. MS:APCl: M+1: 447.2 (Exact mass: 446.19).

Example B17 Synthesis of7-(4-{4-[2-(1,1-Difluoro-ethyl)-phenyl]-piperazin-1-yl}-butoxy)-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-[2-(1,1-difluoro-ethyl)-phenyl]-piperazine to give the title compound(0.45 g, 79%). ¹H-NMR (400 MHz, DMSO-d₆): δ 12.00 (s, 1H), 10.65 (s,1H), 8.00 (d, 1H), 7.81 (d, 1H), 7.58 (m, 2H), 7.50 (m 1H), 7.30 (m 1H),6.70 (d, 1H), 6.40 (d, 1H), 4.40 (t, 2H), 3.60 (m, 2H), 3.30-3.00 (m,8H), 2.10 (t, 3H), 2.00-1.70 (m, 4H).

Example B18 Synthesis of7-{4-[4-(2-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(2-chloro-3-methoxy-phenyl)-piperazine to give the title compound. MS:APCl: M+1: 443.3 (Exact mass: 442.18).

Example B19 Synthesis of7-{4-[4-(2-Chloro-3-ethoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(2-chloro-3-ethoxy-phenyl)-piperazine to give the title compound. MS:APCl: M+1: 457.2 (Exact mass: 456.19).

Example B20 Synthesis of7-{4-[4-(2-Chloro-3-isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(2-chloro-3-isopropoxy-phenyl)-piperazine to give the title compound.MS: APCl: M+1:471.2 (Exact mass: 470.21).

Example B21 Synthesis of7-{4-[4-(3-Methyl-2-phenoxy-phenyl)-piperazin-1yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(3-methyl-2-phenoxy-phenyl)-piperazine to give the title compound. MS:APCl: M+1: 485.2 (Exact mass: 484.25).

Example B22 Synthesis of7-{4-[4-(3-Chloro-2-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(3-chloro-2-fluoro-phenyl)-piperazine to give the title compound. MS:APCl: M+1: 431.2 (Exact mass: 430.16).

Example B23 Synthesis of7-{4-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(2-chloro-4-fluoro-phenyl)-piperazine to give the title compound. MS:APCl: M+1: 431.2 (Exact mass: 430.16).

Example B24 Syntheisis of7-{4-[4-(2,3-Dichloro-4-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(2,3-dichloro-4-fluoro-phenyl)-piperazine to give the title compound.MS: APCl: M+1: 465.1 (Exact mass: 464.12).

Example B25 Synthesis of7-{4-[4-(2-Chloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(2-chloro-phenyl)-piperazine to give the title compound. MS: APCl:M+1: 413.1 (Exact mass: 412.17).

Example B26 Synthesis of7-[4-(4-Biphenyl-2-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-biphenyl-2-yl-piperazine to give the title compound. MS: APCl: M+1:455.0 (Exact mass: 454.24).

Example B27 Synthesis of7-{4-[4-(3-Methoxy-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(3-methoxy-2-methyl-phenyl)-piperazine to give the title compound. MS:APCl: M+1: 423.2 (Exact mass: 422.23).

Example B28 Synthesis of7-{4-[4-(2-Chloro-3-fluoro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(2-chloro-3-fluoro-phenyl)-piperazine to give the title compound. MS:APCl: M+1: 431.2 (Exact mass: 430.16).

Example B29 Synthesis of7-{4-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(6-cyclopropyl-pyridin-2-yl)-piperazine to give the title compound.MS: APCl: M+1: 420.2 (Exact mass: 419.23).

Example B30 Synthesis of7-[4-(4-Pyrimidin-2-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

In a manner similar to that of other examples above,2-piperazin-1-yl-pyrimidine hydrobromide was coupled by reductiveamination to4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followedby typical workup and purification to give the title compound, MS: APCl:M+1: 381.1 (Exact Mass: 380.20).

Example B31 Synthesis of7-{4-[4-(4-Methoxy-pyrimidin-2-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

In a manner similar to that of other examples above,4-methoxy-2-piperazin-1-yl-pyrimidine hydrochloride (US 6,303,603) wascoupled by reductive amination to4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followedby typical workup and purification to give the title compound. MS: APCl:M+1: 411.2 (Exact Mass: 410.21).

Example B32 Synthesis of7-[4-(4-lndan-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-indan-4-yl-piperazine to give the title compound. MS: APCl: M+1: 419.2(Exact mass: 418.24).

Example B33 Synthesis of7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to give the titlecompound. MS: APCl: M+1: 433.3 (Exact mass: 432.25).

Example B34 Synthesis of7-{4-[4-(3-Fluoro-5.6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(3-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to give thetitle compound (0.364 g; 54 %). MS: APCl: M+1: 451.3 (Exact mass:450.24).

Example B35 Synthesis of7-{4-[4-(8-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one to give the titlecompound (0.391 g, 59%). ¹H NMR (400 MHz, CDCl₃): δ 8.89 (br s, 1H),7.71 (d, 1H), 7.63 (d, 1H), 7.33 (t, 1H), 6.90 (d, 1H), 6.82 (d, 1H),6.60 (d, 1H), 6.51 (d, 1H), 4.38 (t, 2H), 3.16-3.04 (m, 4H), 2.93 (t,2H), 2.78-2.68 (m, 4H), 2.63 (t, 2H), 2.56-2.48 (m, 2H), 2.10-2.00 (m,2H), 1.88-1.79 (m, 2H), 1.79-1.67 (m, 2H). MS ES: 447.26 (M+H)⁺ (Exactmass: 446.23).

Example B36 Synthesis of7-{4-[4-(7,7-Dimethyl-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using2,2-dimethyl-8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one to givethe title compound. ¹H NMR (CDCl₃, 400 MHz): δ 9.15 (brs, 1H), 7.75 (d,1H), 7.70 (d, 1H), 7.30 (m, 2H), 6.65 (d, 1H), 6.55 (d, 1H), 6.60 (d,1H), 6.50 (d, 1H), 4.40 (t, 2H), 3.10 (br s, 4H), 2.90 (t, 2H), 2.60 (brs, 4H), 2.50 (br s, 2H), 1.90 (t, 2H), 1.90-1.60 (m, 4H), 1.20 (s, 6H).ESMS: 475.26 (Exact mass: 474.26).

Example B37 Synthesis of7-{4-[4-(7,7-Dimethyl-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(7,7-dimethyl-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to givethe title compound. ¹H NMR (CDCl₃, 400 MHz): δ 9.30 (br s, 1H), 7.75 (d,1H), 7.65 (d, 1H), 7.10 (t, 1H), 6.90 (m, 2H), 6.60 (d, 1H), 6.50 (d,1H), 4.40 (t, 2H), 2.95-2.40 (m, 14H), 1.90(m, 2H), 1.70 (m, 2H), 1.50(m, 2H), 1.00 (s, 6H). ESMS: 461.29 (Exact mass: 460.28).

Example B38 Synthesis of7-{4-[4-(7,7-Difluoro-8-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using2,2-difluoro-8-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one to givethe title compound. ¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (s, 1H), 8.02 (s,1H), 7.84 (d, 1H), 7.60 (t, 1H), 7.09 (d, 1H), 7.06 (d, 1H), 6.64 (d,1H), 6.38 (d, 1H), 4.20 (t, 2H), 3.61 (m, 2H), 3.98-3.03 (m, 13),1.98-1.78 (m, 4H).

Example B39 Synthesis of7-{4-[4-(7,7-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(7,7-difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to givethe title compound (0.329 g, 78%). ¹H NMR (400 MHz, CDCl₃) δ 9.02 (br s,1H), 7.72 (d, 1H), 7.62 (d, 1H), 7.18 (t, 1H), 6.99 (d, 1H), 6.92 (d,1H), 6.60 (d, 1H), 6.52 (d, 1H), 4.39 (t, 2H), 3.23 (t, 2H), 3.01 (t,2H), 2.95-2.84 (m, 4H), 2.74-2.56 (m, 4H), 2.54-2.46 (m, 2H), 2.28-2.13(m, 2H), 1.90-1.81 (m, 2H), 1.79-1.68 (m, 2H). ES MS: 469.27 (M+1)⁺(Exact mass: 468.23).

Example B40 Synthesis of7-{4-[4-(7-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

An intermediate compound,7-{4-[4-(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one,was produced as follows:

1-(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazine (578 mg, 2.37 mmol)and 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (500mg, 2.16 mmol) were dissolved in dichloroethane (10 mL). Triethylamine(655 mg, 6.47 mmol) was added and the mixture was stirred for 10minutes. Sodium triacetoxyborohydride (548 mg, 2.59 mmol) was added andthe mixture was stirred for 1.5 hours. The mixture was quenched withwater (20 mL) and extracted with dichloromethane (20 mL). The organiclayer was washed with brine (20 mL), dried over anhydrous sodiumsulfate, filtered and evaporated. The crude solid was purified by columnchromatography (5:95 triethylamine/ethyl acetate) to yield theintermediate compound (589 mg, 59%) as a white foam. ¹H NMR (400 MHz,CDCl₃) δ 9.40 (s, 1H), 7.75 (d, 1H), 7.60 (d, 1H), 7.18 (t, 1H),7.00-6.90 (m, 2H), 6.60 (d, 1H), 6.54 (d, 1H), 4.80 (t, 1H), 4.40 (t,2H), 3.60 (s, 3H), 3.50-3.48 (m, 2H), 3.44-3.38 (m, 2H), 2.95 (t, 4H),2.80-2.50 (m, 4H), 2.44 (t, 2H), 1.90-1.65 (m, 4H).

7-{4-[4-(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one(360 mg, 0.78 mmol) was dissolved in a mixture of ethanol (6 mL) andtetrahydrofuran (2 mL). To this was added 10% hydrochloric acid (1.5 mL)and the mixture was stirred at room temperature for 15 minutes, thenquenched with saturated sodium bicarbonate (10 mL). The mixture wasextracted with ethyl acetate (20 mL) and the organic layer was washedwith brine (20 mL), dried over anhydrous sodium sulfate, filtered andevaporated. The crude solid was purified by column chromatography (6:94triethylamine/ethyl acetate) to yield the title compound (263 mg, 75%)as a white foam. ¹H NMR (400 MHz, CDCl₃) δ 9.15 (s, 1H), 7.76 (d, 1H),7.60 (d, 1H), 7.20 (t, 1H), 7.00-6.95 (m, 2H), 6.60 (d, 1H), 6.50 (d,1H), 4.40 (t, 2H), 3.60 (s, 2H), 3.04 (t, 2H), 2.90-2.80 (m, 4H),2.80-2.40 (m, 8H), 1.90-1.60 (m, 4H), MS ES+447.05 (M+H)⁺ (Exact mass:446.23).

Example B41 Synthesis of7-{4-[4-(7-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

To a solution of7-{4-[4-(7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one(1.20 g, 2.69 mmol) in methanol (10 mL) was added portionwise NaBH₄(0.41 g, 10.76 mmol). The reaction mixture was stirred at roomtemperature for 30 min and quenched with saturated NH₄CI solution andthe compound was extracted with CH₂Cl₂ (2×20 mL). The organic layer waswashed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andevaporated. The crude product was purified by column chromatography (10%methanol in ethyl acetate) to afford the title compound (0.60 g, 50%),as a white solid. ¹H NMR (400 MHz, CDC1₃) δ 9.25 (s, 1H), 7.72 (d, 1H),7.63 (d, 1H), 7.12 (t, 1H), 6.91 (d, 1H), 6.85 (d, 1H), 6.59 (d, 1H),6.52 (d, 1H), 4.23 (t, 2H), 4.13-4.08 (m, 1H), 3.25-3.20 (m, 1H),3.02-2.83 (m, 6H), 2.61-2.47 (m 6H), 1.88-1.71 (m, 6H). ES MS: 449.26(M+1)⁺ (Exact mass: 448.25).

Example B42 Synthesis of7-{4-[4-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

In a manner similar to that of other examples above,5-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one was coupled byreductive amination to4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followedby typical workup and purification to give the title compound, mp58-160° C. MS: APCl: M+1: 447.3 (Exact Mass: 446.23).

Example B43 Synthesis of7-{4-[4-(5,5-Difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(5,5-difluoro-5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to givethe title compound (0.227 g, 37 %). ¹H NMR (400 MHz, CDCl₃) δ 9.00 (brs, 1H), 7.72 (d, 1H), 7.64 (d, 1H), 7.44 (d, 1H), 7.30 (t, 1H), 7.12 (d,1H), 6.60 (d, 1H), 6.52 (d, 1H), 4.40 (t, 2H), 2.98-2.88 (m, 4H),2.82-2.76 (m, 2H), 2.70-2.54 (m, 4H), 2.48 (t, 2H), 2.36-2.22 (m, 2H),2.00-1.91 (m, 2H), 1.89-1.80 (m, 2H), 1.77-1.66 (m, 2H). ES MS: 469.03(M+H)⁺ (Exact mass: 468.23).

Example B44 Synthesis of7-{4-[4-(3-Oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using7-piperazin-1-yl-indan-1-one to give the title compound. ¹H NMR (400MHz, CDCl₃) δ 8.92 (br s, 1H), 7.72 (d, 1H), 7.64 (d, 1H), 7.45 (t, 1H),6.97 (d, 1H), 6.77 (d, 1H), 6.60 (d, 1H), 6.52 (d, 1H), 4.38 (t, 2H),3.32-3.16 (m, 4H), 3.10-3.02 (m, 2H), 2.80-2.66 (m, 4H), 2.66-2.62 (m,2H), 2.58-2.46 (m, 2H), 1.92-1.80 (m, 2H), 1.80-1.66 (m, 2H). ES MS:432.94 (M+1)⁺ (Exact mass: 432.22).

Example B45 Synthesis of7-{4-[4-(2-Oxo-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using4-piperazin-1-yl-indan-2-one to give the title compound. ¹H NMR (400MHz, CDCl₃): δ: 9.20 (br s, 1H), 7.75 (d, 1H), 7.65 (d, 1H), 7.25 (t,1H), 7.05 (d, 1H), 6.90 (d, 1H), 4.40 (t, 2H), 3.55 (s, 2H), 3.45 (s,2H), 3.05 (br s, 4H), 2.70 (br s, 4H), 2.45 (t, 2H), 1.85 (m, 2H), 1.65(m, 2H). MS ES: m/z 433.21 (M+H)⁺ (Exact mass: 432.22).

Example B46 Synthesis of7-{4-[4-(2,2-Difluoro-indan-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(2,2-difluoro-indan-4-yl)-piperazine to give the title compound (0.208g, 40%). ¹H NMR (400 MHz, CDCl₃): δ: 9.15 (br s, 1H), 7.75 (d, 1H), 7.65(d, 1H), 7.25 (t, 1H), 6.90 (d, 1H), 6.85 (d, 1H), 6.65 (d, 1H), 6.50(d, 1H), 4.40 (t, 2H), 3.35 (m, 4H), 3.05 (br s, 4H), 2.75 (br s, 4H),2.50 (m, 2H), 1.90 (m, 2H), 1.75 (m, 2H). MS ES: m/z 455.11 (M+H)⁺(Exact mass: 454.22).

Example B47 Synthesis of7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

To a mixture of4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (175 mg,0.754 mmol) and 1-naphthalen-1-yl-piperazine hydrochloride (206 mg,0.829 mmol) in DCE (4 mL) was added Et₃N (0.23 mL, 1.66 mmol). Themixture was stirred for 10 min and NaBH(OAc)₃ (224 mg, 1.06 mmol) wasadded as a powder. The reaction was stirred at room temperature for 2 hand then quenched with saturated NaHCO₃. The mixture was extracted withEtOAc. The organic layer was washed with saturated NaHCO₃ and brine,dried over Na₂SO₄ and concentrated to give a white foam. Purification byliquid chromatography (5% MeOH/CH₂Cl₂) gave the title compound as awhite foam (260 mg, 0.607 mmol, 80%). The foam was dissolved in aminimal amount of CH₂Cl₂ and Et₂O was added. 1M HCl in Et₂O (0.6 mL) wasadded and a white precipitate formed. The solid was collected byfiltration, washed with Et₂O and dried to give a white fluffy solid (257mg). MS: APCl: M+1: 429.2 (Exact Mass: 428.22).

Example B48 Synthesis of7-{4-[4-(6-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(6-fluoro-naphthalen-1-yl)-piperazine to give the title compound (195mg, 72%). ¹H NMR (400 MHz, dmso-d₆) δ 12.00 (s, 1H), 8.20-8.15 (m, 1H),8.10 (d, 1H), 7.80 (d, 1H), 7.76-7.60 (m, 2H), 7.60-7.40 (m, 2H), 7.20(d, 1H), 6.65 (d, 1H), 6.40 (d, 1H), 4.40 (t, 2H), 3.70-3.20 (m, 10H),2.00-1.80 (m, 4H), MS ES+447.18 (M+H)⁺ (Exact mass: 446.21).

Example B49 Synthesis of7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(7-fluoro-naphthalen-1-yl)-piperazine to give the title compound (250mg, 85%). ¹H NMR (CDCl₃, 400 MHz) δ 9.02 (s, 1H), 7.82-7.79 (m, 2H),7.75 (d, 1H), 7.62 (d, 1H), 7.58 (d, 1H), 7.36 (t, 1H), 7.30-7.20 (m,1H), 7.18 (d, 1H), 6.60 (d, 1H), 6.56 (d, 1H), 4.40 (t, 2H), 3.20-3.00(m, 4H), 2.90-2.60 (m, 4H), 2.60 (t, 2H), 1.96-1.70 (m, 4H). MS ES+447.17 (M+1)⁺ (Exact mass: 446.21).

Example B50 Synthesis of7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(8-fluoro-naphthalen-1-yl)-piperazine to give the title compound (0.32g, 42%). ¹H NMR (400 MHz, CDCl₃): δ 9.20 (br s, 1H), 7.75 (d, 1H), 7.60(m, 2H), 7.45 (d, 1H), 7.40-7.30 (m, 2H), 7.15-7.05 (m, 2H), 6.60 (d,1H), 6.48 (d, 1H), 4.40 (t, 2H), 3.40-3.25 (m, 2H), 3.05-2.80 (m, 4H),2.60-2.40 (m, 4H), 1.90-1.65 (m, 4H). MS (ES+): 447.17 (M+H)⁺ (Exactmass: 446.21).

Example B51 Synthesis of7-{4-[4-(5-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(5-fluoro-naphthalen-1-yl)-piperazine to give the title compound. ¹HNMR (400 MHz, DMSO-d₆): δ 12.00 (s, 1H), 8.03 (d, J=6.3 Hz, 1H), 7.97(d, J=6.2 Hz, 1H), 7.85 (d, J=6.1 Hz, 1H), 7.75 (d, J=5.8 Hz, 1H), 7.50(m, 2H), 7.35 (m, 1H), 7.22 (d, J=5.5 Hz, 1H), 6.68 (d, J=6.6 Hz, 1H),6.40 (d, J=6.70 Hz, 1H), 4.40 (t, J=3.5 Hz, 2H), 3.00 (s, 4H), 2.70 (s,4H), 2.50 (br s, 2H), 1.80 (m, 2H), 1.60 (m, 2H).

Example B52 Synthesis of7-{4-[4-(4-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(4-fluoro-naphthalen-1-yl)-piperazine to give the title compound. ¹HNMR (400 MHz, CDCl₃): δ 9.20 (br s, 1H), 8.25 (m, 1H), 8.10 (m, 1H),7.75 (d, 1H), 7.62 (d, 1H), 7.58 (dd, 2H), 7.10-6.95 (m, 2H), 6.60 (d,1H), 6.45 (d, 1H), 4.40 (t, 2H), 3.22-3.00 (br s, 4H), 2.85-2.60 (br s,4H), 2.55 (m, 2H), 1.95-1.65 (m, 4H). MS: ES+ 447.23 (M+H)⁺ (Exact mass:446.21).

Example B53 Synthesis of7-{4-[4-(3-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(3-fluoro-naphthalen-1-yl)-piperazine to give the title compound. ¹HNMR (400 MHz, CDCl₃) δ 9.00 (br s, 1H), 8.12 (d, 1H), 7.78-7.70 (m, 2H),7.64 (d, 1H), 7.50-7.38 (m, 2H), 7.14 (dd, 1H), 6.86 (dd, 1H), 6.62 (d,1H), 6.52 (d, 1H), 4.40 (t, 2H), 3.15 (brs, 4H), 2.76 (brs, 4H), 2.56(t, 2H), 1.94-1.84 (m, 2H), 1.81-1.70 (m, 2H). MS (ES+ ): 447.05 (M+H)⁺(Exact mass: 446.21).

Example B54 Synthesis of7-{4-[4-(2-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(2-fluoro-naphthalen-1-yl)-piperazine to give the title compound (175mg, 43%). ¹H-NMR (400 MHz, DMSO-d₆): δ: 12.00 (s, 1H), 8.30 (d, J=6.5Hz, 1H), 7.97 (m, 2H), 7.83 (m, 2H), 7.60-7.30 (m, 3H), 6.65 (d, J=8.2Hz, 1H), 6.40 (d, J=8.0 Hz, 1H), 4.40 (m, 2H), 4.00 (br s, 4H),3.40-3.10 (m, 6H), 2.00-1.77 (m, 4H).

Example B55 Synthesis of7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(6,7-difluoro-naphthalen-1-yl)-piperazine to give the title compound(0.25 g, 70%). ¹H NMR (400 MHz, DMSO-d₆): δ 12.30 (s, 1H), 10.55 (br s,1H), 8.03 (m, 3H), 7.80 (d, 1H), 7.70 (d, 1H), 7.55 (t, 1H), 7.22 (d,1H), 6.65 (d, 1H), 6.40 (d, 1H), 4.40 (t, 2H), 3.70-3.10 (m, 10H),1.90-1.70 (m, 4H).

Example B56 Synthesis of7-{4-[4-(7-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(7-chloro-naphthalen-1-yl)-piperazine to give the title compound(0.373 g, 45%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H), 10.78 (s,1H), 8.12 (d, 1H), 8.01 (t, 2H), 7.85 (d, 1H), 7.74 (d, 1H), 7.58-7.48(m, 2H), 7.28 (d, 1H), 6.68 (d, 1H), 6.37 (d, 1H), 4.40 (t, 2H), 3.64(m, 2H), 3.48-3.19 (m, 8H), 1.98-1.81 (m, 4H).

Example B57 Synthesis of7-{4-[4-(6-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(6-chloro-naphthalen-1-yl)-piperazine to give the title compound(0.403 g, 48%). mp. 208-209° C. ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s,1H), 8.16 (d, 1H), 8.06 (d, 1H), 8.02 (d, 1H), 7.83 (d, 1H), 7.64 (d,1H), 7.55 (m, 2H), 7.22 (d, 1H), 6.64 (d, 1H), 6.39 (d, 1H), 4.40 (t,2H), 3.62 (m, 2H), 3.53-3.09 (m, 8H), 1.98-1.73 (m, 4H).

Example B58 Synthesis of7-{4-[4-(5-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(5-chloro-naphthalen-1-yl)-piperazine to give the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H), 8.18 (d, 1H), 8.01 (d, 1H), 7.98(d, 1H), 7.83 (d, 1H), 7.77 (d, 1H), 7.63 (t, 1H), 7.54 (t, 1H),7.32 (d,1H), 6.68 (d, 1H), 6.38 (dd, 1H), 4.40 (t, 2H), 3.64 (m, 2H), 3.48-3.15(m, 8H), 1.98-1.81 (m, 4H).

Example B59 Synthesis of7-{4-[4-(8-Chloro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(8-chloro-naphthalen-1-yl)-piperazine to give the title compound(0.257 g, 41%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 1H), 8.02 (d, 1H),7.92 (dd, 1H), 7.84 (d, 1H), 7.76 (d, 1H), 7.62 (dd, 1H), 7.54 (t, 1H),7.46 (t, 1H), 7.32 (dd, 1H), 6.66 (d, 1H), 6.38 (d, 1H), 4.38 (t, 2H),3.62 (m, 2H), 3.55-3.24 (m, 6H), 3.12 (m, 2H), 1.96-1.78 (m, 4H).

Example B60 Synthesis7-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(7-methoxy-naphthalen-1-yl)-piperazine to give the title compound. ¹HNMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 7.78-7.74 (m, 2H), 7.62 (d, 1H),7.60-7.40 (m, 2H), 7.26-7.24 (m, 1H), 7.18-7.06 (m, 2H), 6.60 (d, 1H),6.50 (d, 1H), 4.40 (t, 2H), 3.90 (s, 3H), 3.30-2.80 (m, 8H), 2.60 (t,2H), 1.90-1.65 (m, 4H). MS ES+459.21 (M+1)⁺ (Exact mass: 458.23).

Example B61 Synthesis of7-{4-[4-(6-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(6-methoxy-naphthalen-1-yl)-piperazine to give the title compound. ¹HNMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 8.10 (d, 1H), 7.74 (d, 1H), 7.60(d, 1H), 7.40 (d, 1H), 7.38 (t, 1H), 7.18-7.10 (m, 2H), 6.98 (d, 1H),6.60 (d, 1H), 6.50 (d, 1H), 4.40 (t, 2H), 3.90 (s, 3H), 3.20-2.80 (m,8H), 2.58 (t, 2H), 1.90-1.65 (m, 4H). MS ES+ 459.20 (M+H)⁺ (Exact mass:458.23).

Example B62 Synthesis of7-{4-[4-(7-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(8-piperazin-1-yl-naphthalen-2-yl)-ethanone to give the title compound(400 mg, 83%). ¹H NMR (400 MHz, dmso-d₆) δ 12.00 (s, 1H), 8.70 (s, 1H),8.10-8.00 (m, 3H), 7.85 (d, 1H), 7.80 (d, 1H), 7.60 (t, 1H), 7.30 (d,1H), 6.65 (d, 1H), 6.40 (d, 1H), 4.40 (t, 2H) 3.70-3.60 (m, 2H),3.60-3.20 (m, 8H), 2.80 (s, 3H), 2.00-1.80 (m, 4H), MS ES+ 471.23 (M+H)⁺(Exact mass: 470.23).

Example B63 Synthesis of7-{4-[4-(6-Acetyl-naphthalen-1-yl)-piierazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(5-piperazin-1-yl-naphthalen-2-yl)-ethanone to give the title compound(300 mg, 85%). ¹H NMR (400 MHz, dmso-d₆) δ 12.00 (s, 1H), 8.64 (s, 1H),8.20 (d, 1H), 8.05-7.95 (m, 2H), 7.90-7.80 (m, 2H), 7.60 (t, 1H), 7.36(d, 1H), 6.64 (d, 1H), 6.40 (d, 1H), 4.40 (t, 2H), 3.70-3.60 (m, 2H),3.50-3.32 (m, 4H), 3.30-3.10 (m, 4H), 2.70 (s, 3H), 2.00-1.80 (m, 4H),MS ES+ 471.17 (M+H)⁺ (Exact mass: 470.23).

Example B64 Synthesis of7-{4-[4-(5-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(5-piperazin-1-yl-naphthalen-1-yl)-ethanone to give the title compound(0.39 g, 77%). ¹H NMR (400 MHz, CDCl₃): δ 8.45 (d, J=7.7 Hz, 1H), 8.30(d, J=7.6 Hz, 1H), 7.90 (d, J=5.8 Hz, 1H), 7.75 (m, 2H), 7.55 (m, 2H),7.30 (d, J=6.2 Hz, 1H), 6.70 (m, 2H), 4.50 (t, J=3.6 Hz, 2H), 4.00-3.60(m, 4H), 3.40-3.10 (m, 4H), 2.80 (s, 3H), 2.30 (m, 2H), 2.00 (m, 4H).

Example B65 Synthesis of7-{4-[4-(4-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(4-piperazin-1-yl-naphthalen-1-yl)-ethanone to give the title compound(0.42 g, 69%). ¹H NMR (400 MHz, DMSO-d₆): δ 12.00 (s, 1H), 10.60 (s,1H), 8.80 (d, 1H), 8.15 (m, 2H), 8.00 (d, 1H), 7.80 (d, 1H), 7.60 (m,2H), 7.20 (d, 1H), 6.63 (d, 1H), 6.40 (d, 1H), 4.40 (m, 2H), 3.80-3.20(m, 10H), 2.70 (s, 3H), 2.00-1.80 (m, 4H).

Example B66 Synthesis of7-{4-[4-(2-Acetyl-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1 was followed using1-(1-piperazin-1-yl-naphthalen-2-yl)-ethanone to give the titlecompound. ¹H NMR (400 MHz, CDCl₃): δ 12.00 (s, 1H), 8.37 (m, 1H), 7.80(m, 2H), 7.60 (m, 3H), 6.70 (d, J=8.8 Hz, 1H), 6.40 (d, J=8.6 Hz, 1H),4.40 (m, 2H), 3.60-3.40 (m, 10H), 2.66 (s, 3H), 1.90 (m, 4H).

Example B67 Synthesis of8-{4-[4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyl]-piperazin-1-yl}-naphthalene-2-carbonitrile

The reductive amination procedure from Example B1 was followed using8-piperazin-1-yl-naphthalene-2-carbonitrile to give the title compound(0.341 g, 24%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 1H), 11.24 (s,1H), 8.63 (s, 1H), 8.13 (d, 1H), 8.20 (d, 1H), 7.83 (m, 2H), 7.70 (t,1H), 7.37 (d, 1H), 6.68 (d, 1H), 6.38 (d, 1H), 4.40 (t, 2H), 3.68-3.21(m, 16H), 2.40-1.90 (m, 4H).

Example B68 Synthesis of1-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

An intermediate compound, 7-Chloro-1-methyl-1H-[1,8]naphthyridin-2-one,was produced as follows: To a suspension of7-chloro-1H-[1,8]naphthyridin-2-one (1.17 g, 6.49 mmol) in THF (32 mL)cooled to 0° C. was added potassium teit-butoxide (1 M in THF, 9.7 mL,9.7 mmol). After stirring for 15 min, Mel (0.81 mL, 13.0 mmol) wasadded. The reaction was stirred at 0° C. for 1 h and at room temperaturefor 5 h. The reaction was quenched with saturated NH₄Cl and H₂O. Themixture was extracted with EtOAc. The organic layer was washed withsaturated NaHCO₃ and brine, dried over Na₂SO₄ and concentrated.Purification by liquid chromatography (Analogix, RS-120, 10-50%EtOAc/Hexanes) gave the intermediate compound as a white solid (0.88 g,4.52 mmol, 70%). MS: APCl: M+1: 195.0 (Exact Mass: 194.02).

To a solution of 4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (422mg, 1.48 mmol) in THF (5 mL) cooled to 0° C. was added7-chloro-1-methyl-1H-[1,8]naphthyridin-2-one (303 mg, 1.56 mmol) as asolution in THF (9 mL) via cannula. The reaction was stirred for about 2h at 0° C. The reaction was quenched with saturated NH₄Cl and themixture was extracted with EtOAc. The organic layer was washed withsaturated NaHCO₃ and brine, dried over Na₂SO₄ and concentrated.Purification by LC (4% MeOH/CH₂Cl₂) gave the title compound as a whitefoam (507 mg, 1.15 mmol, 77%). A portion of the title compound (243 mg,0.549 mmol) was dissolved in Et₂O and 1 N HCl in Et₂O (0.55 mL) wasadded. The resulting white precipitate was collected by filtration,washed with Et₂O and dried to give a white solid (248 mg). MS: APCl:M+1: 443.3 (Exact Mass: 442.24).

Example C1 Synthesis of7-{3-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-propoxy}-1H-[1,8]naphthyridin-2-one

An intermediate compound,2-Benzyloxy-7-{3-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-propoxy}-[1,8]naphthyridine,was produced as follows: To a suspension of3-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-propan-1-ol hydrochloride(400 mg, 1.23 mmol) in THF (5 mL) cooled to −40° C. was added KO^(t)Bu(1 M in THF, 2.3 mL, 2.3 mmol, 1.9 equiv). The mixture became a cloudysolution. After stirring for 20 min at −40° C.,2-benzyloxy-7-chloro-[1,8]naphthyridine (333 mg, 1.23 mmol) was added asa solution in THF (8 mL) via cannula. The reaction was allowed to warmto 0° C. slowly over 1 h. The reaction was quenched with saturated NH₄Cland H₂O and extracted with EtOAc. The organic layer was washed withsaturated NaHCO₃ and brine, dried over Na₂SO₄ and concentrated.Purification by liquid chromatography (CH₂Cl₂ to 2% MeOH/CH₂Cl₂) gavethe title compound as a clear oilfoam (367 mg, 0.701 mmol, 57%). MS:APCl: M+1: 523.0 (Exact Mass: 522.16).

2-Benzyloxy-7-{3-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-propoxy}-[1,8]naphthyridine(367 mg, 0.701 mmol) was hydrogenated using 5% Pd/C (0.1 g) in MeOH (50mL) for 1 h. The reaction was filtered and concentrated. Purification byliquid chromatography (4-5% MeOH/CH₂Cl₂) gave the title compound as awhite foam (181 mg, 0.418 mmol, 60%). MS: APCl: M+1: 433.1 (Exact Mass:432.11).

Example C2 Synthesis of7-[3-(4-Naphthalen-1-yl-piperazin-1-yl)-propoxyl]-1H-[1,8]naphthyridin-2-one

A first intermediate compound,4-(3-Hydroxy-propyl)-piperazine-1-carboxylic acid tert-butyl ester, wasproduced as follows: A 12 L, 4-necked RB flask, equipped with amechanical stirrer, thermometer, nitrogen inlet and an addition funnelis charged with a solution of N-boc-piperazine, (600 g, 3.225 mol) inDMF (3.9 L) followed by anhydrous potassium carbonate (666 g, 4.82 mol)then sodium iodide (72.5 g, 1.25 mol). The reaction mixture is stirredat ˜80° C. for 16 h, cooled to room temperature, filtered, washed withDMF (2×200 mL) and evaporated to a thick mass, which is set aside for aday at ˜5° C. The solids are filtered, washed with hexanes (3×300 mL)and dried in vacuum at ˜50° C. to get 438 g crude as a white powder. Thecrude compound is dissolved in 10% methanol in ether (2.5 L) and passedthrough a small silica gel column (previously washed with ethercontaining 2% triethylamine). The filtrates are evaporated to thickliquid and added to a mixture of hexanes-ether (2:1, 2.5 L) whilestirring and continued the stirring for 12 h at ˜5° C., filtered, washedwith hexanes and dried the product to give the title compound, as awhite crystalline solid (308 g, 39%).

A second intermediate compound,4-[3-(7-Benzyloxy-[1,8]naphthyridin-2-yloxy)-propyl]-piperazine-1-carboxylicacid tert-butyl ester, was produced as follows: A 5 L 4-necked flask,equipped with a mechanical stirrer, thermometer, nitrogen inlet and anaddition funnel is charged with a solution of4-(3-hydroxy-propyl)-piperazine-1-carboxylic acid tert-butyl ester, (129g, 0.528 mol) in anhydrous THF (1.6 L) and cooled to −40° C. To thispotassium tert-butoxide solution (580 mL, 1M in THF, 0.58 mol) is addeddrop-wise during 1 h, and stirred further for 30 min.2-Benzyloxy-7-chloro-[1,8]naphthyridine (130 g, 0.48 mol) is added tothe reaction mixture in portions at −40° C. during 1 h. The reaction isstirred for 4 h to bring to 0° C., then quenched with saturated ammoniumchloride solution (1.5 L) and extracted with ethyl acetate (2 L and 1L). The combined organic extracts are washed with brine (1 L), driedover anhydrous sodium sulfate and concentrated to afford the crude as adark brown thick paste. The crude is purified by silica gelchromatography using 20-25% ethyl acetate in hexanes for elution to givethe second intermediate compound as a thick almost colorless thick paste(126 g, 49.8%).

A third intermediate compound,4-[3-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-propyl]-piperazine-1-carboxylicacid tert-butyl ester, was produced as follows: To a solution of4-[3-(7-benzyloxy-[1,8]naphthyridin-2-yloxy)-propyl]-piperazine-1-carboxylicacid tert-butyl ester (62 g, 0.129 mol) in methanol (600 mL) and THF(150 mL) is added 10% Pd/C (6 9) and the mixture is hydrogenated atatmospheric pressure at room temperature for 20 h. The reaction mixtureis filtered, washed with methanol, concentrated and vacuum dried at ˜50°C. to afford the third intermediate compound as a pale yellow thickgummy solid (48.8 g, 94%).

A fourth intermediate compound,7-(3-Piperazin-1-yl-propoxy)-1H-[1,8]naphthyridin-2-one, was produced asfollows: A 2 L, 3-necked RB flask, equipped with mechanical stirrer anda nitrogen inlet is charged with a solution of4-[3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-propyl]-piperazine-1-carboxylicacid tert-butyl ester (43.4 g, 0.111 mol) in dichloromethane (500 mL)followed by trifluoroacetic acid (187 mL) at room temperature. Thereaction mixture is stirred at room temperature by occasionallyevacuating the reaction flask with vacuum. After ensuring the absence ofstarting material by TLC (10% methanol in CH₂Cl₂), the solvents areremoved by co-distilling with toluene (3×). The residue is triturated inether to obtain 62 g of the crude as a TFA salt. The crude TFA salt issuspended in water (50 mL), basified with 4N NaOH (100 mL), stirred,washed with CH₂Cl₂ and passed through a column of HP-20 (300 mL)previously washed with methanol followed by water. The column isthoroughly washed with water to eliminate any basic impurities andeluted with methanol. The methanol solution thus obtained is evaporatedand the residue is triturated in ether to afford the fourth intermediatecompound as an off-white powder (33 g, 100%), m.p.192-195° C.

7-(3-Piperazin-1-yl-propoxy)-1H-[1,8]naphthyridin-2-one (1.5 g, 4.2mmol) was placed in a 25 mL flask with 15 mL toluene and azeotroped todryness. The mixture was cooled to 25° C. and 1-bromo-naphthalene (4.45g, 21 5 mmol) was added. In a separate flask, Pd(OAc)₂ (0.073 g, 0.325mmol) and 2-dicyclohexylphosphino biphenyl (0.180 g, 0.514 mmol) weredissolved in degassed anhydrous toluene (3 mL). This solution was thenadded to the suspension of the two reactants via syringe. Sodiumtert-butoxide, (0.8 g, 8.32 mmol) was added which gave a suspension uponstirring. After the mixture had been heated to reflux overnight, themixture was evaporated and the residue was taken up into dichloromethaneand water. The pH was adjusted to 4.5 with 1N citric acid followed byseparation of the aqueous phase. The organic phase was washed with waterand the pH adjusted to 12 by addition of 1N sodium hydroxide and brine.The organic phase was separated, dried over sodium sulfate, filtered andevaporated to an oil with suspended solids. The residue was purified bychromatography on silica gel eluting with dichloromethane and then agradient to 20% methanol in ethyl acetate. The title compound wasrecovered as a crystalline solid (0.262 g). MS: APCl: M+1: 415.5 (ExactMass: 414.21).

Example C3 Synthesis of7-[3-(4-Naphthalen-1-yl-piperazin-1-yl)-propoxyl]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,4-[3-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-propyl]-piperazine-1-carboxylicacid tert-butyl ester, was produced as follows: To a solution of4-[3-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-propyl]-piperazine-1-carboxylicacid tert-butyl ester (62 g, 0.129 mol) in methanol (600 mL) and THF(150 mL) is added 10% Pd/C (6 g) and the mixture is hydrogenated atatmospheric pressure at room temperature for 20h. The reaction mixtureis filtered, washed with methanol, concentrated and vacuum dried at ˜50°C. to afford 43 g of a pale yellow thick gummy solid. It is againsubjected to hydrogenation by dissolving in DMF-dioxane-ethanol (0.3 L:1L:0.2 L) and adding fresh Pd/C (8 g). After a similar workup, the firstintermediate compound was obtained as a thick gum (37 g, 73.5%).

A second intermediate,7-(3-Piperazin-1-yl-propoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one, wasproduced as follows: A 2 L, 3-necked RB flask, equipped with amechanical stirrer, and a nitrogen inlet is charged with a solution of4-[3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-propyl]-piperazine-1-carboxylicacid tert-butyl ester (35 g, 0.089 mol) in dichloromethane (500 mL)followed by trifluoroacetic acid (150 mL) at room temperature. Thereaction mixture is stirred at room temperature by occasionallyevacuating the reaction flask with vacuum. After ensuring the absence ofstarting material by TLC (10% methanol in CH₂Cl₂), the solvents areremoved by co-distilling with toluene (3×) to get the crude TFA salt asa light brown thick paste. The crude material is suspended in water (50mL), basified with 4N NaOH (100 mL), stirred, filtered, washedthoroughly with water followed by ether and dried under vacuum over P₂O₅at ˜50° C. to afford the second intermediate compound as an off-whitepowder (24.4 g, 93%), m.p. 142-46° C.

In a similar manner to the example shown above,7-(3-piperazin-1-yl-propoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one wascoupled to 1-bromo-naphthalene to give the title compound (0.189 g). MS:APCl: M+1: 417.2 (Exact Mass: 416.22).

Example C4 Synthesis of7-{2-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-ethoxy}-1H-[1,8]naphthyridin-2-one

An intermediate compound,2-Benzyloxy-7-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethoxy}-[1,8]naphthyridine,was produced as follows: To a solution of2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethanol (1.0 g, 3.63 mmol) inTHF (6 mL) cooled to −20° C. was added 1M KO^(t)BU in THF (3.6 mL, 3.6mmol). After 15 min, a solution of2-benzyloxy-7-chloro-[1,8]naphthyridine (1.18 g, 4.35 mmol, 1.2 equiv)in THF (25 mL) was added quickly via cannula. The reaction became abrown solution. The reaction was slowly allowed to warm to 0° C. over 90min and then quenched with saturated NH₄Cl and H₂O. The mixture wasextracted with EtOAc. The organic layer was washed with saturated NaHCO₃and brine, dried over Na₂SO₄ and concentrated. Purification by liquidchromatography (CH₂Cl₂ to 2% MeOH/CH₂Cl₂) gave the product with somelower R_(f) impurities. Further purification by liquid chromatography(75% EtOAc/Hexanes) afforded the intermediate compound as a clearoivwhite foam (1.36 g, 2.67 mmol, 74%). MS: APCl: M+1: 509.0 (ExactMass: 508.14).

2-Benzyloxy-7-{2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethoxy}-[1,8]naphthyridine(1.30 g, 2.55 mmol) was hydrogenated using 5% Pd/C (0.4 g) in MeOH (100mL) for 40 min. The reaction was filtered and concentrated. Purificationby liquid chromatography (2-3% MeOH/EtOAc with 1% NH₄OH) gave the titlecompound as a white foam (600 mg, 1.43 mmol, 56%). The HCl salt wasprepared using 1N HCl in Et₂O to give a white solid. MS: APCl: M+1:419.1 (Exact Mass: 418.10).

Example C5 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-1-methyl-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,2-Benzyloxy-7-[4-(tert-butyl-dimethyl-silanyloxy)-1-methyl-butoxy]-[1,8]naphthyridine,was produced as follows: To a solution of the5-(tert-butyl-dimethyl-silanyloxy)-pentan-2-ol (1.61 g, 7.39 mmol,Tetrahedron Lett. 1979, 99) in THF (7 mL) cooled to −30° C. was added 1MKO^(t)Bu in THF (7.4 mL, 7.4 mmol). The solution was stirred for 15 minand 2-benzyloxy-7-chloro-[1,8]naphthyridine (2.0 g, 7.39 mmol) was addedas a solution in THF (40 mL). The reaction was allowed to warm to roomtemperature over 6 h. The reaction was quenched with saturated NH4Cl andH2O and extracted with EtOAc. The organic layer was washed withsaturated NaHCO3 and brine, dried over Na2SO4 and concentrated.Purification by liquid chromatography (5% EtOAc/Hexanes) gave the firstintermediate compound as a clear oil (1.77 g, 3.91 mmol, 53%). MS: APCl:M+1: 453.2 (Exact Mass: 452.25).

A second intermediate compound,4-(7-Benzyloxy-[1,8]naphthyridin-2-yloxy)-pentan-1-ol, was produced asfollows: To a solution of2-benzyloxy-7-[4-(tert-butyl-dimethyl-silanyloxy)-1-methyl-butoxy]-[1,8]naphthyridine(1.77 g, 3.91 mmol) in THF (8 mL) was added 1 M TBAF in THF (7.8 mL, 7.8mmol). The reaction turned purple instantly. The reaction was stirred atroom temperature for 1 h. Saturated NaHCO₃ was added and the mixture wasextracted with EtOAc. The organic layer was washed with H₂O and brine,dried over Na₂SO₄ and concentrated to give a pale brown oil.Purification by liquid chromatography (35-40% EtOAc/Hexanes) gave thesecond intermediate compound as a clear oil (1.29 g, 3.81 mmol, 97%).

A third intermediate compound,7-(4-Hydroxy-1-methyl-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows:4-(7-Benzyloxy-[1,8]naphthyridin-2-yloxy)-pentan-1-ol (1.29 g, 3.81mmol) was hydrogenated using 20% Pd/C (0.35 g) in MeOH (50 mL) for 18 h.The reaction was filtered and concentrated. Purification by liquidchromatography (5% MeOH/CH₂Cl₂) gave the third intermediate compound asa clear oil (0.898 g, 3.59 mmol, 94%).

A fourth intermediate compound,4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-pentanal, wasproduced as follows: To a cloudy solution of the Dess-Martin reagent(2.28 g, 5.38 mmol) in CH₂Cl₂ (10 mL) was added7-(4-hydroxy-1-methyl-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.895 g, 3.59 mmol) as a solution in CH₂Cl₂ (10 mL). The reactionturned clear and then became pale yellow. The reaction was stirred atroom temperature for 6 h. Saturated NaHCO₃ and saturated Na₂S₂O₃ (1:1)was added and the mixture was stirred for 10 min. The mixture wasextracted with EtOAc/Et₂O (2×). The organic layer was washed withsaturated NaHCO₃, H₂O and brine, dried over MgSO₄ and concentrated togive a brown oil (901 mg, used crude in subsequent reductiveaminations). MS: APCl: M+1: 249.1 (Exact Mass: 248.12).

To a solution of4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-pentanal (450 mg,crude) in DCE (10 mL) was added 2,3-dichlorophenyl-piperazinehydrochloride (495 mg, 1.85 mmol) followed by Et₃N (0.55 mL, 3.96 mmol).The mixture was stirred for 10 min and then powdered NaBH(OAc)₃ (534 mg,2.52 mmol) was added. The reaction was stirred at room temperature for 2h and then quenched with saturated NaHCO₃. The mixture was extractedwith EtOAc (2×). The organic layer was washed with saturated NaHCO₃ andbrine, dried over Na₂SO₄ and concentrated to give a foam. Purificationby liquid chromatography (4% MeOH/CH₂Cl₂) gave the title compound as awhite foam (507 mg, 1.09 mmol, 61%). MS: APCl: M+1: 463.1 (Exact Mass:462.16). The enantiomers were separated by chiral HPLC (Chiralcel OD).

Example C6 Synthesis of7-[1-Methyl-4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The procedure above was followed using 1-naphthalen-1-yl-piperazinehydrochloride (460 mg, 1.85 mmol). Purification by liquid chromatography(4% MeOH/CH₂Cl₂) gave the title compound as a white foam (539 mg, 1.21mmol, 67%). MS: APCl: M+1: 445.2 (Exact Mass: 444.25). The enantiomerswere separated by chiral HPLC (Chiralcel OD).

Example C7 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-1-dimethyl-butoxy}-3,4-dihVdro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,2-Benzyloxy-7-[4-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-butoxy]-[1,8]naphthyridine,was produced as follows: To a mixture of the5-(tert-butyl-dimethyl-silanyloxy)-2-methyl-pentan-2-ol (3.0 g, 12.91mmol, J. Org. Chem. 1997, 62, 3153 and Tetrahedron Lett. 1979, 99) and2-benzyloxy-7-chloro-[1,8]naphthyridine (3.49 g, 12.91 mmol) in THF (100mL) cooled to 0° C. was added KHMDS (0.5 M in toluene, 25.8 mL, 12.91mmol). The reaction turned dark green. After 30 min at 0° C., the icebath was removed and the reaction was stirred for 2 h at RT. SaturatedNH₄Cl was added and the mixture was extracted with CH₂Cl₂ (2×). Theorganic layer was washed with saturated NH₄Cl and concentrated to give adark orange oil. Purification by liquid chromatography (5%EtOAc/Hexanes) gave the first intermediate compound as a clear oil (1.64g, 3.51 mmol, 27%). MS: APCl: M+1: 467.1, fragment: 253.1 (Exact Mass:466.27).

A second intermediate compound, 7-(4-Hydroxy-1,1-dimethyl-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was producedas follows:2-Benzyloxy-7-[4-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-butoxy]-[1,8]naphthyridine(1.64 g, 3.51 mmol) was hydrogenated using 20% Pd/C (0.5 g) in MeOH (50mL) for 22 h. The TBS group was removed under the reaction conditions.The reaction was filtered and concentrated. The residue was dissolved inEtOAc and washed with saturated NaHCO₃ and brine. The organics wereconcentrated and purified by liquid chromatography (5% MeOH/CH₂Cl₂) togive the second intermediate compound as a clear oil which solidifiedunder vacuum to give a white solid (648 mg, 2.45 mmol, 70%). MS: APCl:M+1: 265.1 (Exact Mass: 264.15).

A third intermediate compound,4-Methyl-4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-pentanal,was produced as follows: To a cloudy solution of the Dess-Martin reagent(1.66 g, 3.92 mmol) in CH₂Cl₂ (10 mL) was added7-(4-hydroxy-1,1-dimethyl-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one(648 mg, 2.45 mmol) as a solution in CH₂Cl₂ (5 mL). The reaction wasstirred at room temperature for 5 h. Saturated NaHCO₃ and saturatedNa₂S₂O₃ (1:1) was added and the mixture was stirred for 10 min. Themixture was extracted with EtOAc/Et₂O (2×). The organic layer was washedwith saturated NaHCO₃, H₂O and brine, dried over MgSO₄ and concentratedto give a yellow solid/oil (679 mg, used crude in subsequent reductiveaminations). MS: APCl: M+1: 263.1 (Exact Mass: 262.13).

To a solution of4-methyl-4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-pentanal(335 mg, crude) in DCE (6 mL) was added 2,3-dichlorophenyl-piperazinehydrochloride (335 mg, 1.25 mmol) followed by Et₃N (0.35 mL, 2.50 mmol).The mixture was stirred for 10 min and then powdered NaBH(OAc)₃ (365 mg,1.72 mmol) was added. The reaction was stirred at room temperature for 2h and then quenched with saturated NaHCO₃. The mixture was extractedwith EtOAc (2×). The organic layer was washed with saturated NaHCO₃, H₂Oand brine, dried over Na₂SO₄ and concentrated. Purification by liquidchromatography (4% MeOH/CH₂Cl₂) gave the title compound as a white foam(395 mg, 0.827 mmol, 67% over 2 steps). The foam was dissolved in Et₂Oand 1N HCl in Et₂O (0.85 mL) was added. The resulting white precipitatewas collected by filtration, washed with Et₂O and dried to give a whitesolid (386 mg). MS: APCl: M+1: 477.1 (Exact Mass: 476.17).

Example C8 Synthesis of7-[1,1-Dimethyl-4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3.4-dihydro-1H-[1,8]naphthyridin-2-one

The procedure above was followed using 1-naphthalen-1-yl-piperazinehydrochloride (311 mg, 1.25 mmol). Purification by liquid chromatography(4% MeOH/CH₂Cl₂) gave the title compound as a white foam (384 mg, 0.837mmol, 68% over 2 steps). The HCl salt was prepared as above to give awhite solid (385 mg). MS: APCl: M+1: 459.2 (Exact Mass: 458.27).

Example C97-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,7-Amino-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was produced as follows:A solution of 7-amino-[1,8]naphthyridin-2-ol-H₂SO₄ (36.0 g, 139 mmol, J.Org. Chem. 1981, 46, 833) in 6 N HCl (600 mL) was hydrogenated using 20%Pd/C for 2 d. The reaction was filtered and then cooled to −50° C. Athick white precipitate formed which was filtered and washed with Et₂O.The resulting solid was slurried with Et₂O, filtered and dried to givethe first intermediate compound as the hydrochloride salt (21.5 g, 108mmol, 78%). MS: APCl: M+1: 164.0 (Exact Mass: 163.07).

A second intermediate compound,7-Chloro-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was produced asfollows: To concentrated HCl (80 mL) cooled to −5° C. and saturated withHCl gas was added 7-amino-3,4-dihydro-1H-[1,8]naphthyridin-2-one (9.0 g,55.0 mmol) to give a solution. A solution of NaNO₂ (9.6 g, 137.0 mmol)in H₂O (15 mL) was added subsurface via a syringe pump over 20 min. Thetemperature was between −5 to −7° C. The mixture was a yellow-orangesuspension during the addition and turned dark green after the addition.The reaction was poured into saturated NaHCO₃ (500 mL) at 10° C. andadditional solid NaHCO₃ was added to bring pH to 7. The mixture wasextracted with EtOAc. The organic layer was dried over MgSO₄ andconcentrated. The residue was dissolved in warm EtOAc (125 mL) and theinsoluble material was filtered off. The filtrate was washed withsaturated Na₂CO₃, dried over MgSO₄ and concentrated to a smaller volume.The resulting solid was filtered and dried to give the secondintermediate compound (4.4 g, 24.2 mmol, 44%). MS: APCl: M+1: 183.0(Exact Mass: 182.02).

A third intermediate compound,7-(5-Chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one, wasproduced as follows: To a solution of7-chloro-3,4-dihydro-1H-[1,8]naphthyridin-2-one (9.0 g, 49.0 mmol) indimethoxyethane (160 mL) was added Pd(PPh3)4 (1.60 g, 1.48 mmol)followed by a slurry of 5-chloro-1-pentenyl boronic acid (10.97 g, 74.0mmol) in dimethoxyethane (20 mL). A solution of Na2CO3 (10.7 g) in H2O(50 mL) was added and the mixture was heated overnight at 85° C. MorePd(PPh3)4 (0.44 g) was added and the reaction was heated at 104° C.overnight. The reaction was complete. The reaction was cooled to roomtemperature and the organic layer was separated. The organic layer wascooled to −10° C. and a precipitate formed. The solid was filtered offand the filtrate was concentrated to give a brown oil. The oil wasdissolved in Et2O, washed with 2N NaOH and brine, dried over MgSO4 andconcentrated to give a solid. Et2O (450 mL) was added and a yellow solidremained insoluble which was filtered off. The filtrate was treated withcharcoal and concentrated to give a solid. The solid was washed withcold Et2O and dried to give the third intermediate compound as a whitesolid (7.97 g, 49.0 mmol, 71%). mp 70-73° C. MS: APCl: M+1: 251.1 (ExactMass: 250.09).

A fourth intermediate compound,7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: To a mixture of 2,3-dichlorophenylpiperazine(2.2 g, 9.52 mmol) and7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (2.15 g,8.58 mmol) in CH₃CN (20 mL) was added a solution of K₂CO₃ (2.5 g, 18.1mmol) in H₂0 (10 mL) followed by Kl (0.1 g). The reaction was heated at78° C. for 3 d. The reaction was about 50% complete so it was heated bymicrowave at 120° C. for 90 min. The reaction was allowed to cool toroom temperature and solids precipitated. The mixture was cooled in therefrigerator. The solids were collected by filtration and washed withH₂O and brine. The solids were dissolved in EtOAc, washed with saturatedNaHCO₃ and brine, and dried over MgSO₄. The solution was concentrated toa reduced volume and the resulting white precipitate was filtered andwashed with Et₂O to give a white solid. Recrystallization from CH₃CNgave the fourth intermediate compound as a white solid (2.08 g, 4.57mmol, 54%). MS: APCl: M+1: 445.1 (Exact Mass: 444.15).

7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one(1.85 g, 4.16 mmol) was hydrogenated using Ra-Ni (1 g) in EtOH/THF (50mL) for 1.4 h. The reaction was filtered and concentrated to give asolid. Recrystallization from hot CH₃CN gave the title compound as awhite solid (1.58 g, 3.54 mmol, 85%). MS: APCl: M+1: 447.1 (Exact Mass:446.16).

Example C10 Synthesis of7-{5-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound,7-{5-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-pent-l-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: To a solution of Na₂CO₃ (0.28 g, 2.6 mmol) inH₂O (2 mL) was added 2-chloro-3-methylphenylpiperazine hydrochloride(0.311 g, 1.26 mmol) and7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.30 g,1.20 mmol) followed by a catalytic amount of Nal. The mixture was heatedat 95° C. overnight. After cooling to RT, the solid was washed severaltimes with H₂O and dried over a stream of N₂. Purification by liquidchromatography (SiO₂, 5% EtOH/CH₂Cl₂ to 5% MeOH/CH₂Cl₂) gave theintermediate compound (471 mg, 1.11 mmol, 92%). MS: APCl: M+1: 425.2(Exact Mass: 424.20).

7-{5-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.322 g, 0.758 mmol) was hydrogenated using Ra-Ni (0.5 g) in 1:1EtOH/THF (50 mL) for 21 h. The reaction was filtered and concentrated.Purification by liquid chromatography (SiO2, 5% MeOH/CH2Cl2 to 7%MeOH/CH2Cl2) gave the title compound as a light yellow foam (282 mg,0.660 mmol, 87%). MS: APCl: M+1: 427.3 (Exact Mass: 426.22).

Example C11 Synthesis of7-{5-[4-(2,3-Dichloro-4-fluoro-phenyl)-piperazin-1-yl]pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound,7-{5-[4-(2,3-Dichloro-4-fluoro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was produced as follows: To a mixture of7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (500 mg,1.99 mmol) and 4-fluoro-2,3-dichlorophenylpiperazine bishydrochloride(805 mg, 2.50 mmol, 1.25 equiv) in CH₃CN (10 mL) was added K₂CO₃ (1.10g, 7.98 mmol, 4 equiv) followed by Kl (66 mg, 0.40 mmol, 0.2 equiv). Thereaction was refluxed for 2 d. H₂O was added to dissolve the salts andthe mixture was extracted with EtOAc. The organic layer was washed withsaturated NaHCO₃ and brine, dried over Na₂SO₄ and concentrated.Purification by liquid chromatography (4% MeOH/CH₂Cl₂) gave theintermediate compound as a white foam (768 mg, 1.66 mmol, 83%). MS:APCl: M+1: 463.1 (Exact Mass: 462.14).

7-{5-[4-(2,3-Dichloro-4-fluoro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one(633 mg, 1.37 mmol) was hydrogenated using Ra-Ni (0.65 g) in 1:1EtOH/THF (50 mL) for 21 h. The reaction was filtered and concentrated.Purification by liquid chromatography (4% MeOH/CH₂Cl₂) gave a white foam(425 mg). The foam was dissolved in CH₃CN and the compound crystallized.The solid was collected by filtration, washed with Et₂O and dried togive the title compound as a white solid (366 mg, 0.786 mmol, 57%). MS:APCl: M+1: 465.1 (Exact Mass: 464.15).

Example C12 Synthesis of7-{15-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,1-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazine, was produced asfollows: To a reaction flask containing a solution of5,6,7,8-tetrahydro-naphthalen-1-ylamine (10.0 g, 67.9 mmol) inchlorobenzene (10 mL), was added bis-(2-chloro-ethyl)-amine hydrochoride(12.12 g, 67.92 mmol). The reaction was refluxed for 14 hours. Thereaction was cooled and the precipitate was filtered. The filtrate waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over Na₂SO₄, and concentrated. Purification bychromatography on silica gel (0-40% MeOH/CH₂Cl₂) afforded the firstintermediate compound as a grayish white solid (8.25 g, 56%). MS: APCl:M+1: 217.2 (Exact Mass: 216.16).

A second intermediate compound,7-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: To a flask containing a solution of7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.330g, 1.19 mmol) in CH₃CN (8 ml) was added1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine (0.388 g, 1.79 mmol),followed by K₂CO₃ (0.328 g, 2.38 mmol) and Kl (0.039 g, 0.238 mmol). Thereaction was refluxed for 18 hours. The reaction was cooled to roomtemperature and partitioned between EtOAc and aqueous NaHCO₃. Theorganic layer was washed with brine, dried over Na₂SO₄ and concentratedto give an oil. Purification by chromatography on silica gel (0-10%MeOH/EtOAc) afforded the second intermediate compound as a white foam(0.308 g, 60%). A small portion (81 mg) was then dissolved in Et₂O and1M HCl in Et₂O (1 equiv) was added. A precipitate formed and wasfiltered. The product was a white solid (90 mg). MS: APCl: M+1: 431.3(Exact Mass: 430.27).

7-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.225 g, 0.523 mmol) was hydrogenated using Ra-Ni (0.25 g) in THF for16 hours. The reaction was filtered and concentrated to give a foam.This was dissolved in Et₂O and 1M HCl in Et₂O (1 equiv) was added. Theprecipitate was filtered and dried to give the title compound as a whitesolid (0.157 g, 70%). MS: APCl: M+1: 433.4 (Exact Mass: 432.29).

Example C13 Synthesis of7-[5-(4-Naphthalen-1-yl-piperazin-1-yl)-pentyl]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound,7-[5-(4-Naphthalen-1-yl-piperazin-1-yl)-pent-1-enyl]-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: Reaction of7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one with1-naphthalen-1-yl-piperazine according to the procedure in Example C9gave the intermediate compound (0.340 g, 0.80 mmol, 50%). MS: APCl: M+1:427.2 (Exact Mass: 426.24).

Hydrogenation of7-[5-(4-naphthalen-1-yl-piperazin-1-yl)-pent-1-enyl]-3,4-dihydro-1H-[1,8]naphthyridin-2-oneaccording to the procedure in Example C9 gave the title compound (0.250g, 0.48 mmol, 75%). MS: APCl: M+1: 429.3 (Exact Mass: 428.26).

Example C14 Synthesis of7-{5-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-pentyl}-3.4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound,7-{5-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: To a flask containing a solution of7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.300g, 1.19 mmol) in CH₃CN (8 mL) and H₂O (3 mL), was added1-(2-chloro-4-fluoro-phenyl)-piperazine (0.516 g, 1.79 mmol), followedby K₂CO₃ (0.493 g, 3.57 mmol) and Kl (0.027 g, 0.238 mmol). The reactionwas refluxed for 12 hours. The reaction was cooled to room temperature,diluted with EtOAc and washed with NaHCO₃ and brine. The organic layerwas dried over Na₂SO₄ and concentrated to give an oil. Purification bychromatography on silica gel (0-10% MeOH/EtOAc) afforded theintermediate compound as a white foam (0.363 g, 71%). A small portion(93 mg) was then dissolved in Et₂O and 1M HCl in Et₂O (1 equiv) wasadded. A precipitate formed which was filtered and dried to give a whitesolid (97 mg). MS: APCl: M+1: 429.2 (Exact Mass: 428.18).

7-{5-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.268 g, 0.623 mmol) was hydrogenated using Ra-Ni (0.2 g) in THF for 13hours. The reaction was filtered and concentrated to give an oil. Et₂Owas added and the product crashed out. The mixture was filtered anddried to give the title compound as a white solid (0.214 g, 80%). MS:APCl: M+1: 431.3 (Exact Mass: 430.19).

Example C15 Synthesis7-{5-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-oneof

An intermediate compound,7-{5-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one, was produced as follows: To a solution of Na₂CO₃(93 mg, 0.88 mmol) in H₂O (2 mL) was added2-chloro-4-fluoro-3-methylphenylpiperazine hydrochloride (106 mg, 0.40mmol) and7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (100 mg,0.40 mmol) followed by a catalytic amount of Nal. The mixture was heatedat 95° C. overnight. After cooling to RT, the solid was washed severaltimes with H₂O and dried over a stream of N₂. Purification by liquidchromatography (SiO₂, 5% EtOH/CH₂Cl₂ to 5% MeOH/CH₂Cl₂) gave theintermediate compound (134 mg, 0.303 mmol, 76%). MS: APCl: M+1: 443.2(Exact Mass: 442.19).

7-{5-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.382 g, 0.862 mmol) was hydrogenated using Ra-Ni(0.5 g) in 1:1 EtOH/THF (50 mL) for 12 h. The reaction was filtered andconcentrated. Purification by liquid chromatography (SiO2, 5%MeOH/CH2Cl2 to 7% MeOH/CH2Cl2) gave the title compound as a light yellowfoam (342 mg, 0.769 mmol, 89%). MS: APCl: M+l: 445.2 (Exact Mass:444.21).

Example C16 Synthesis of7-{5-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound,7-{5-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: To a solution of K₂CO₃ (1.16 g, 8.38 mmol) inH₂O (3 mL) was added CH₃CN (9 mL), 1-(6-methyl-pyridin-2-yl)-piperazine(0.84 g, 3.35 mmol) and7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.70 g,2.80 mmol) followed by a catalytic amount of Kl (8 mg). The mixture wasstirred for 15 min and then heated in a microwave (300 W) at 120° C. for150 min. After cooling to RT, saturated NaHCO₃ was added and the mixturewas extracted with EtOAC. The organic layer was washed with brine, driedover MgSO₄ and concentrated to give a yellow oil. Purification by liquidchromatography (40M Biotage SiO₂ column, CH₂Cl₂ to 2% MeOH/CH₂Cl₂) gavethe intermediate compound as a foam (426 mg, 1.09 mmol, 39%). MS: APCl:M+1: 392.1 (Exact Mass: 391.24).

7-{5-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.343 g, 0.876 mmol) was hydrogenated using 20% Pd/C in EtOH for 103 h.The reaction was filtered and concentrated. Purification by liquidchromatography (Biotage 12 SiO₂ column, CH₂Cl₂ to 1% MeOH/CH₂Cl₂)followed by recrystallization from Et₂O gave the title compound as awhite powder (42 mg, 0.01 mmol, 12%). MS: APCl: M+1: 394.2 (Exact Mass:393.25).

Example C17 Synthesis of7-{5-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound,7-{5-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: To a solution of K₂CO₃ (1.16 g, 8.38 mmol) inH₂O (3 mL) was added CH₃CN (9 mL), 1-(6-ethyl-pyridin-2-yl)-piperazine(0.64 g, 3.36 mmol) and7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.70 g,2.80 mmol) followed by a catalytic amount of Kl (8 mg). The mixture wasstirred for 15 min and then heated in a microwave (300 W) at 120° C. for150 min. After cooling to RT, saturated NaHCO₃ was added and the mixturewas extracted with EtOAC. The organic layer was washed with brine, driedover MgSO₄ and concentrated to give a yellow oil. Purification by liquidchromatography (40M Biotage SiO₂ column, CH₂Cl₂ to 1% MeOH/CH₂Cl₂) gavethe intermediate compound (845 mg, 2.08 mmol, 74%). MS: APCl: M+1: 406.3(Exact Mass: 405.25).

7-{5-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.515 g, 1.27 mmol) was hydrogenatedusing 20% Pd/C in EtOH for 103 h. The reaction was filtered andconcentrated. Purification by liquid chromatography (Biotage 12 SiO₂column, CH₂Cl₂ to 1% MeOH/CH₂Cl₂) followed by recrystallization fromEt₂O gave the title compound as a solid (50 mg, 0.012 mmol, 10%). MS:APCl: M+1: 408.2 (Exact Mass: 407.27).

Example C18 Synthesis of7-{5-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound,7-{5-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: To a solution of K₂CO₃ (1.16 g, 8.38 mmol) inH₂O (6 mL) was added CH₃CN (9 mL),1-(6-cyclopropyl-pyridin-2-yl)-piperazine (0.68 g, 3.35 mmol) and7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.70 g,2.80 mmol). The mixture was stirred for 15 min and then heated in amicrowave (300 W) at 120° C. for 150 min. After cooling to RT, saturatedNaHCO₃ was added and the mixture was extracted with EtOAC. The organiclayer was washed with brine, dried over MgSO₄ and concentrated to give ayellow oivfoam. Purification by liquid chromatography (40M Biotage SiO₂column, CH₂Cl₂ to 2% MeOH/CH₂Cl₂) gave the intermediate compound as ayellow oiVfoam (443 mg, 1.06 mmol, 38%). MS: APCl: M+1: 418.3 (ExactMass: 417.25).

7-{5-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.347 g, 0.831 mmol) was hydrogenated using 20% Pd/C in THF for 15 h.The reaction was filtered and concentrated. Recrystallization from hotCH₃CN gave the title compound as a white powder (288 mg, 0.686 mmol,83%). MS: APCl: M+1: 420.3 (Exact Mass: 419.27).

Example C19 Synthesis of7-{5-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound,7-{5-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: To a solution of K₂CO₃ (1.16 g, 8.38 mmol) inH₂O (3 mL) was added CH₃CN (9 mL),1-(4,6-dimethyl-pyridin-2-yl)-piperazine (0.909 g, 3.34 mmol) and7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.70 g,2.80 mmol) followed by a catalytic amount of Kl (8 mg). The mixture wasstirred for 15 min and then heated in a microwave (300 W) at 120° C. for150 min. After cooling to RT, saturated NaHCO₃ was added and the mixturewas extracted with EtOAC. The organic layer was washed with brine, driedover MgSO₄ and concentrated to give a yellow oiVfoam. Purification byliquid chromatography (40M Biotage SiO₂ column, CHCl₃ to 1% MeOH/CHCl₃)gave the intermediate compound as a foam (540 mg, 1.33 mmol, 48%). MS:APCl: M+1: 406.2 (Exact Mass: 405.25).

7-{5-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.54 g, 1.33 mmol) was hydrogenated using 20% Pd/C in EtOH for 58 h.The reaction was filtered and concentrated. Purification by liquidchromatography (Biotage 12 SiO₂ column, CHCl₃ to 1% MeOH/CHCl₃) followedby recrystallization from Et₂O/hexanes gave the title compound as anoff-white solid (313 mg, 0.761 mmol, 57%). MS: APCl: M+1: 408.2 (ExactMass: 407.27).

Example C20 Synthesis of7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-1H-[1,8]naphthyridin-2-one

A first intermediate compound, 7-Chloro-1H-[1,8]naphthyridin-2-one, wasproduced as follows: To a stirred solution of lithiumhexamethyldisilazane (26.3 mmol, 1.0 M in THF) in THF (10 mL) at −78° C.is added t-butyl acetate (3.53 mL, 26.3 mmol) dropwise. The mixture isstirred at −78° C. for 30 min andN-(6-chloro-3-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (3.00 g,12.5 mmol) in THF (20 mL) is added dropwise. A yellow precipitate formsand the mixture is stirred at −78° C. for 30 minutes and warmed to roomtemperature over 3 hours. H₂O (10 mL) is added, the mixture stirred for5 minutes and then diluted with ethyl acetate (20 mL) and brine (10 mL).The organic layer is separated, washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The compound isrecrystallized from ethyl acetate and hexanes to yield3-[6-chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-propionicacid tert-butyl ester (3.52 g, 79%); mp 130-132° C., ¹H NMR (400 MHz,CDCl₃) δ 8.25 (br s, 1H), 7.76 (d, 1H), 7.16 (d, 1H), 5.05-4.98 (m, 1H),4.08 (d, 1H), 2.80 (dd, 1H), 2.70 (dd, 1H), 1.41 (s, 9H), 1.36 (s, 9H);MS ES+ 357.03 (M+H)⁺.

3-[6-Chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-propionicacid tert-butyl ester (15.43 g, 43.3 mmol) is dissolved in dioxane (60mL) and 3 N HCl (60 mL) is added. The mixture is refluxed for 4 hours,cooled to room temperature, and poured over ice. The resultingprecipitate is filtered, washed with H₂O (2×20 mL) and dried to affordthe first intermediate compound (7.80 g, >99%); mp 258-259° C., ¹H NMR(400 MHz, DMSO-d₆) δ 12.38 (br s, 1H), 8.14 (d, 1H), 7.94 (d, 1H), 7.30(d, 1H), 6.54 (d, 1H); MS ES+180.76 (M⁺) (Exact Mass: 180.01).

A second intermediate compound,7-(5-Chloro-pent-1-enyl)-1H-[1,8]naphthyridin-2-one, was produced asfollows: 7-Chloro-1H-[1,8]naphthyridin-2-one (0.10 g, 0.56 mmol) isdissolved in dioxane (4 mL) and Pd(Ph₃P)₄ (19 mg, 0.02 mmol) is added.The solution is stirred for 5 minutes at room temperature and5-chloro-1-pentenylboronic acid (0.13 g, 0.84 mmol) is added followedimmediately by aqueous Na₂CO₃ (2 mL, 2 M). The mixture is heated at 100°C. for 18 hours. The mixture is cooled to RT, filtered through Celiteand diluted with ethyl acetate (10 mL). The organic layer is washed withbrine (10 mL), dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by column chromatography (ethylacetate) to yield the second intermediate compound (45 mg, 33%); mp125-127° C., ¹H NMR (200 MHz, CDCl₃) δ 9.35 (br s, 1H), 7.80 (d, 1H),7.65 (d, 1H), 7.05 (d, 1H), 6.70 (dt, 1H), 6.60 (d, 1H), 6.55 (d, 1H),3.60 (t, 2H), 2.60-2.40 (m, 2H), 2.10-1.90 (m, 2H), MS ES+ 248.79 (M⁺)(Exact Mass: 248.07).

A third intermediate compound,7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-1H-[1,8]naphthyridin-2-one,was produced as follows: Sodium iodide (2.18 g, 14.52 mmol) is added toa stirred solution of7-(5-chloro-pent-1-enyl)-1H-[1,8]naphthyridin-2-one (1.8 g, 7.26 mmol)in CH₃CN (40 mL). The mixture is refluxed for 1 hour and cooled to roomtemperature. Triethylamine (2.20 g, 21.78 mmol) and1-(2,3-Dichlorophenyl)piperazine monohydrochloride (2.91 g, 10.9 mmol)are added and the mixture is refluxed for 5 hours and cooled to RT. Themixture is filtered and the solids are washed with ethyl acetate (10mL). The filtrate is diluted with ethyl acetate (20 mL), washed withsaturated NH₄Cl (20 mL), saturated NaHCO₃ (20 mL), water (20 mL), andbrine (20 mL). The organic layer is dried over Na₂SO₄, filtered andconcentrated under vacuum. The crude solid is purified by columnchromatography (triethylamine/CH₂Cl₂, 5:95) to yield the thirdintermediate compound as an orange solid (700 mg, 22%). mp 176-178° C.¹H NMR (400 MHz, CDCl₃) δ 8.98 (s, 1H), 7.80 (d, 1H), 7.66 (d, 1H),7.20-7.10 (m, 3H), 7.00-6.85 (m, 2H), 6.62 (d, 1H), 6.53 (d, 1H),3.20-3.00 (m, 4H), 2.76-2.60 (m, 4H), 2.50 (t, 2H), 2.40-2.36 (m, 2H),1.82-1.75 (m, 2H). MS ES+ 443.06 (M⁺) (Exact mass: 442.13).

7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-1H-[1,8]naphthyridin-2-one(160 mg, 0.361 mmol) was hydrogenated using Raney Nickel (0.2 g) in MeOHfor 42 h. The reaction was filtered and concentrated. Purification byliquid chromatography (5% MeOH/CH₂Cl₂ with 1% NH₄OH) gave the titlecompound as a white foam (109 mg, 0.245 mmol, 68%), which was furtherpurified by HPLC to remove a small amount of over-reduced side-product.MS: APCl: M-1: 443.1 (Exact Mass: 444.15).

Example D1 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4-methyl-1H-[1,8]naphthyridin-2-one

A first intermediate compound,7-Chloro-4-methyl-1H-[1,8]naphthyridin-2-one, was produced as follows: Asolution of tert-butyl acetate (0.6 mL, 4.45 mmol) is added dropwise toa solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 4.2 mL,4.2 mmol) in THF (5 mL) at −78 ° C. The yellow solution is stirred for 1hour and N-(3-acetyl-6-chloro-pyridin-2-yl)-2,2-dimethyl-propionamide(0.503 g, 1.97 mmol) in THF (5 mL) is added dropwise to the mixture. Theyellow suspension is stirred at −78 ° C. for 30 minutes and warmed toRT. The suspension clears to a yellow solution and the mixture isstirred at room temperature for 1.5 hours. The mixture is quenched withwater and extracted with CH₂Cl₂. The organic extracts are washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo to a brownliquid. The liquid is purified by column chromatography (2:1hexanes/ethyl acetate) to afford3-[6-chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-butyricacid tert-butyl ester (0.548 g, 75%) as a yellow oil. ¹H NMR (CDCl₃, 400MHz): δ 10.40 (br s, 1H), 7.37 (d, 1H), 6.98 (d, 1H), 5.61 (s, 1H), 3.03(d, 1H), 2.67 (d, 1H), 1.56 (s, 3H), 1.45 (s, 9H), 1.32 (s, 9H). MS ES:m/z=370.86, 372.56.

A light yellow solution of3-[6-chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-butyricacid tert-butyl ester (0.473 9, 1.28 mmol) in 3N HCl (10 mL) and dioxane(10 mL) is refluxed for 1 hour. The yellow mixture is cooled to roomtemperature and extracted with Et₂O. The aqueous layer is separated andneutralized with Na₂CO₃. A white solid separates out of solution and thesolid is collected by filtration to afford the first intermediatecompound (0.232 g, 94%) as a white solid. mp 238-239° C. ¹H NMR(DMSO-d₆, 400 MHz): δ 12.20 (brs, 1H), 8.14 (d, 1H), 7.31 (d, 1H), 6.45(d, 1H), 2.39 (d, 3H). MS ES: m/z=194.74,196.62.

A second intermediate compound,2-Benzyloxy-7-chloro-4-methyl-[1,8]naphthyridine, was produced asfollows: A mixture of 7-chloro-4-methyl-1H-[1,8]naphthyridin-2-one(0.208 g, 1.07 mmol), silver carbonate (0.176 g, 0.64 mmol), and benzylbromide (0.15 mL, 1.26 mmol) in toluene (5 mL) is heated at 70° C.overnight. The grey suspension is filtered through Celite and the yellowfiltrate is concentrated under vacuum to a yellow solid. The solid ispurified by column chromatography (3:1 hexanes/ethyl acetate) to affordthe second intermediate compound (0.196 g, 64%) as an off-white solid.mp 150-151° C. ¹H NMR (CDCl₃, 400 MHz): δ 8.19 (d, 1H), 7.53-7.48 (m,2H), 7.43-7.34 (m, 4H), 6.92-6.90 (s, 1H), 5.61 (s, 2H), 2.67 (s, 3H).MS ES: m/z=285.02, 287.03.

A third intermediate compound,2-Benzyloxy-7-(4-benzyloxy-butoxy)-4-methyl-[1,8]naphthyridine, wasproduced as follows: A mixture of 4-benzyloxy-1-butanol (1.40 mL, 7.96mmol) in THF (20 mL) is treated with potassium tert-butoxide (0.892 g,7.95 mmol). The yellow solution is stirred for 15 minutes at RT.2-Benzyloxy-7-chloro-4-methyl-[1,8]naphthyridine (1.84 g, 6.46 mmol) inTHF (20 mL) is added to the mixture at −40° C. The dark red/brownmixture is warmed to room temperature and stirred for 10 minutes. Themixture is quenched with saturated NaHCO₃ solution (20 mL) and extractedwith ethyl acetate (3×30 mL). The organic extracts are washed with brine(30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to abrown residue. The residue is purified by column chromatography (5:1hexanes/ethyl acetate) to afford the third intermediate compound (1.146g, 41%) as a yellow liquid. ¹H NMR (CDCl₃, 400 MHz): δ 8.08, (d, 1H),7.54-7.48 (m, 2H), 7.42-7.26 (m, 8H), 6.84 (d, 1H), 6.75 (s, 1H), 5.60(s, 2H), 4.59 (t, 2H), 4.54 (s, 2H), 3.58 (t, 2H), 2.58 (s, 3H),2.00-1.90 (m, 2H), 1.90-1.80 (m, 2H). MS ES: m/z=428.92 (MH⁺).

A fourth intermediate compound,7-(4-Hydroxy-butoxy)-4-methyl-1H-[1,8]naphthyridin-2-one, was producedas follows: Hydrogen gas (35 psi) is applied to a mixture of2-benzyloxy-7-(4-benzyloxy-butoxy)-4-methyl-[1,8]naphthyridine (1.188 g,2.77 mmol), 10% Pd/C (wet, 0.364 g) and methanol (160 mL) in a Parrbottle under agitation for 4.5 hours. The catalyst is filtered through apad of Celite and the pad is rinsed with methanol. The filtrate isconcentrated under vacuum to afford the fourth intermediate compound(0.580 g, 84%) as a white solid. mp 172-173° C. ¹H NMR (DMSO-d₆, 400MHz): δ 11.79 (br s, 1H), 8.02 (d, 1H), 6.65 (d, 1H), 6.25 (s, 1H), 4.47(t, 1H), 4.33 (t, 2H), 3.45 (q, 2H), 2.36 (s, 3H), 1.82-1.72 (m, 2H),1.60-1.50 (m, 2H).

Alternatively, a mixture of 1,4-butanediol (0.177 g, 1.96 mmol) in THF(2 mL) is placed in a sealed glass pressure tube. The mixture is treatedwith potassium tert-butoxide (0.252 g, 2.25 mmol) and the cloudy whitesuspension is stirred at room temperature for 15 minutes. The suspensionis treated with 7-chloro-4-methyl-1H-[1,8]naphthyridin-2-one (0.100 g,0.51 mmol) in THF (2 mL). The pressure tube is sealed and heated at 100°C. for 16 hours. The mixture is cooled to room temperature and dilutedwith saturated NaHCO₃ solution (10 mL) and extracted with CH₂Cl₂ (2×30mL). The organic extracts are washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under vacuum to a white residue. Theresidue is purified by column chromatography (5:95 methanovchloroform)to afford the fourth intermediate compound (0.081 g, 63%) as a whitesolid. mp 172-173° C. ¹H NMR (DMSO-d₆, 400 MHz): δ 11.79 (br s, 1H),8.02 (d, 1H), 6.65 (d, 1H), 6.25 (s, 1H), 4.47 (t, 1H), 4.33 (t, 2H),3.45 (q, 2H), 2.36 (s, 3H), 1.82-1.72 (m, 2H), 1.60-1.50 (m, 2H). MS ES:m/z=248.90 (MH⁺).

A fifth intermediate compound,4-(5-Methyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde,was produced as follows: A mixture of Dess-Martin periodinane (1.764 g,4.16 mmol) in CH₂Cl₂ (30 mL) is treated with7-(4-hydroxy-butoxy)-4-methyl-1H-[1,8]naphthyridin-2-one (0.798 g, 3.21mmol) in THF (10 mL) at RT. The slightly cloudy yellow solution isstirred for 2 hours, diluted with Et₂O and poured into a solution ofaqueous saturated NaHCO₃ solution (20 mL) containing sodium thiosulfate(3.8 g, 24.0 mmol). The immiscible solution is stirred for 5 minutes andthe organic layer is separated out. The aqueous layer is extracted withEt₂O. The combined organic extracts are washed with brine, dried overNa₂SO₄, filtered and concentrated under vacuum to a white solid. Thecrude aldehyde is used directly in the next step without purification.

The crude4-(5-methyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefrom the previous reaction in 1,2-dichloroethane (30 mL) is treated with1-(2,3-dichlorophenyl)piperazine monohydrochloride (1.144 g, 4.20 mmol),followed by triethylamine (0.90 mL, 6.46 mmol) and sodiumtriacetoxyborohydride (0.955 g, 4.50 mmol). The cloudy yellow solutionis stirred at room temperature for 1 hour. The mixture is quenched withH₂O and saturated NaHCO₃ solution and extracted with CH₂Cl₂. The organicextracts are washed with brine, dried over Na₂SO₄, filtered andconcentrated under vacuum to a yellow oil. The oil is purified by columnchromatography (5:95 methanovethyl acetate) to afford the title compound(0.97 g, 63% over 2 steps) as a white solid. mp 181-182° C. ¹H NMR(CDCl₃, 400 MHz): δ 7.57 (br s, 1H), 7.40 (d, 1H), 7.18-7.12 (m, 2H),7.00-6.94 (m, 1H), 6.38 (d, 1H), 4.23 (t, 2H), 3.16-3.00 (m, 5H),2.77-2.68 (m, 4H), 2.75-2.56 (m, 1H), 2.52-2.36 (m, 3H), 1.86-1.75 (m,2H), 1.75-1.64 (m, 2H), 1.28 (d, 3H). MS ES: m/z=460.70, 462.58.

Example D2a and D2 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A First intermediate compound,7-(4-Hydroxy-butoxy)-4-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: Hydrogen gas (40 psi) is applied to a mixtureof 7-(4-hydroxy-butoxy)-4-methyl-1H-[1,8]naphthyridin-2-one (0.640 g,2.58 mmol), 10% Pd/C (wet, 0.310 g) and methanol (160 mL) in a Parrbottle under agitation overnight. The catalyst is filtered through a padof Celite and the pad is rinsed with methanol. The filtrate isconcentrated under vacuum to a colorless semi-solid. The semi-solid ispurified by column chromatography (5:95 methanovchloroform) to affordthe first intermediate compound (0.510 g, 79%) as a white solid. Mp99-100° C. ¹H NMR (CDCl₃, 400 MHz): δ 7.60 (br s, 1H), 7.40 (d, 1H),6.39 (d, 1H), 4.24 (t, 2H), 3.77-3.68 (m, 2H), 3.11-3.00 (m, 2H),2.77-2.68 (m, 2H), 2.46-2.37 (m, 2H), 1.50 (br s, 1H), 1.24 (d, 3H). MSES: m/z=250.89 (MH⁺).

A second intermediate compound,4-(5-Methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde,was produced as follows: A mixture of Dess-Martin periodinane (1.511 g,3.56 mmol) in CH₂Cl₂ (30 mL) is treated with7-(4-hydroxy-butoxy)-4-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.742 g, 2.96 mmol) in THF (10 mL) at RT. The slightly cloudy yellowsolution is stirred for 2 hours, diluted with Et₂O and poured into asolution of aqueous saturated NaHCO₃ (20 mL) containing sodiumthiosulfate (3.5 g, 21.1 mmol). The immiscible solution is stirred for 5minutes and the organic layer is separated out. The aqueous layer isextracted with Et₂O. The combined organic extracts are washed withbrine, dried over Na₂SO₄, filtered and concentrated under vacuum to ayellow solid. The crude aldehyde is used directly in the next stepwithout purification.

The crude4-(5-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydein 1,2-dichloroethane (50 mL) is treated with1-(2,3-dichlorophenyl)piperazine monohydrochloride (1.104 g, 4.13 mmol),followed by triethylamine (0.80 mL, 5.69 mmol) and sodiumtriacetoxyborohydride (0.911 g, 4.30 mmol). The cloudy yellow solutionis stirred at room temperature for 1 hour. The mixture is quenched withwater and saturated NaHCO₃ solution and extracted with CH₂Cl₂. Theorganic extracts are washed with brine, dried over Na₂SO₄, filtered andconcentrated under vacuum to a yellow oil. The oil is purified by columnchromatography (5:95 methanoVethyl acetate) to afford the title compound(1.08 g, 79% over 2 steps) as a white solid. Mp 53-54° C. ¹H NMR (CDCl₃,400 MHz): 6 8.94 (br s, 1H), 7.83 (d, 1H), 7.18-7.13 (m, 2H), 6.98-6.94(m, 1H), 6.62 (d, 1H), 6.38 (d, 1H), 4.38 (t, 2H), 3.16-3.02 (m, 4H),2.76-2.60 (m, 4H), 2.55-2.46 (m, 2H), 1.90-1.82 (m, 2H), 1.77-1.64 (m,2H). MS ES: m/Z=462.72, 464.58.

The enantiomers were separated by chiral HPLC (Chiralcel OD) to give theenantiomers D2a and D2 b.

Example D3 Synthesis of7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-4-methyl-1H-[1,8]naphthyridin-2-one

A first intermediate compound,7-(5-Chloro-pent-1-enyl)-4-methyl-1H-[1,8]naphthyridin-2-one, wasproduced as follows: To a solution of7-chloro-4-methyl-1H-[1,8]naphthyridin-2-one (1.01 g, 5.20 mmol) indioxane was added Pd(PPh₃)₄ (234 mg, 0.20 mmol) followed by5-chloro-1-pentenyl boronic acid (1.21 g, 8.10 mmol). Na₂CO₃ (1.21 g,11.40 mmol) and water (2 mL) were added and the resulting mixture wasrefluxed overnight. The orange heterogeneous mixture was cooled to roomtemperature and some crystals precipitated out of solution. The mixturewas filtered and the filtrate was partitioned between EtOAc and water.The organic layer was dried over Na₂SO₄ and concentrated to give ayellow solid. Recrystallization from EtOAc/Hexanes afforded the firstintermediate compound as a golden solid (815 mg, 60%). mp 137-138° C; ¹HNMR (CDCl₃, 400 MHz): δ 9.00 (br s, 1H), 7.88 (d, 1H), 7.13 (d, 1H),6.94-6.82 (m, 1H), 6.58-6.46 (m, 2H), 3.61 (t, 2H), 2.52-2.42 (m, 2H),2.45 (d, 3H), 2.06-1.98 (m, 2H); MS ES: m/z=263.02, 265.00.

A second intermediate compound,7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4-methyl-1H-[1,8]naphthyridin-2-one,was produced as follows: A mixture of7-(5-chloro-pent-1-enyl)-4-methyl-1H-[1,8]naphthyridin-2-one (500 mg,1.90 mmol) and Kl (316 mg, 1.90 mmol) was refluxed for 30 min. Themixture was cooled to room temperature and then treated with1-(2,3-dichlorophenyl)piperazine monohydrochloride (630 mg, 2.40 mmol)followed by K₂CO₃ (611 mg, 4.40 mmol). The yellow suspension wasrefluxed for 2 d and then quenched with water. The mixture was extractedwith EtOAc. The organic layer was washed with brine, dried over Na₂SO₄and concentrated to give a yellow oil. Purification by columnchromatography (5% MeOH/EtOAc) afforded the second intermediate compoundas a yellow solid (371 mg, 42%). mp 198-199° C.; ¹H NMR (CDCl₃, 400MHz): δ 9.03 (brs, 1H), 7.84 (d, 1H), 7.18-7.12 (m, 3H), 7.00-6.92 (m,2H), 6.59-6.46 (m, 2H), 3.16-3.02 (m, 4H), 2.74-2.60 (m, 4H), 2.54-2.47(m, 2H), 2,45 (d, 3H), 2.40-2.32 (m, 2H), 1.83-1.72 (m, 2H); MS ES:m/z=457.40, 459.35.

7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4-methyl-1H-[1,8]naphthyridin-2-one(880 mg, 1.92 mmol) was dissolved in THF (50 mL) and added to a Parrbottle containing a suspension of Raney-Nickel (1.5 mL of a settledsuspension in water) in EtOH (50 mL). The mixture was hydrogenated at 45psi for 5.5 h. The reaction was not complete so additional Raney-Nickel(1 mL of a suspension in water) was added and the mixture washydrogenated at 45 psi for 2.5 h. The reaction mixture was filteredthrough a bed of Celite and washed with EtOH. The filtrate wasconcentrated to give a white solid. Purification by columnchromatography (10% MeOH/EtOAc) afforded the title compound as a whitesolid (780 mg, 88%). mp 195-196° C.; ¹H NMR (CDCl₃, 400 MHz): δ 9.16 (brs, 1H), 7.88 (d, 1H), 7.18-7.12 (m, 2H), 7.06 (d, 1H), 7.00-6.92 (m,1H), 6.50 (s, 1H), 3.14-3.00 (m, 4H), 2.85 (t, 2H), 2.72-2.54 (m, 4H),2.46 (d, 3H), 2.42 (t, 2H), 1.85-1.72 (m, 2H), 1.64-1.52 (m, 2H),1.48-1.36 (m, 2H); MS ES: m/z=459.08, 461.03.

Example D4 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-methyl-1H-[1,8]naphthyridin-2-one

A first intermediate compound,7-Chloro-3-methyl-1H-[1,8]naphthyridin-2-one, was produced as follows:Diisopropyl amine (freshly distilled over sodium, 12.8 mL, 91.4 mmol,2.2 equiv.) was dissolved in Et₂O (40 mL) and cooled to −78° C. Butyllithium (2.5 M solution in hexane, 37.0 mL, 91.4 mmol, 2.2 equiv.) wasadded slowly under nitrogen atmosphere. The mixture was stirred for 15min and t-butyl propionate (13.8 mL, 91.4 mmol, 2.2 equiv.) was added asa solution in dry THF (20 mL). The reaction mixture was stirred for 30min and N-(6-chloro-3-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide(10.0 g, 42.0 mmol, 1.0 equiv.) was added as a solution in a minimumamount of dry THF (35 mL). A bright yellow precipitate was formed within10 min and stirring became difficult. The reaction was allowed to warmup to RT. The reaction mixture turned dark red and was poured intosaturated NH₄Cl (100 mL). The organic layer was separated and theaqueous layer was extracted with CH₂Cl₂. The combined organic layerswere dried over Na₂SO₄ and concentrated.3-[6-Chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2-methyl-propionic acid tert-butyl ester was obtained as a yellowthick syrup which upon drying under high vacuum became a foamy solid(20.0 g, crude). The product was used in the next step without furtherpurification.

3-[6-Chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2-methyl-propionicacid tert-butyl ester (20.0 g) was dissolved in dioxane (100 mL) and 3NHCI (100 mL) was added. The mixture was stirred under reflux conditions.After 30 min, more dioxane (15 mL) was added as there was someprecipitation in the reaction mixture and the resultant clear solutionwas refluxed overnight. The reaction mixture was cooled in a cold waterbath, diluted with 20 mL water and neutralized with saturated K₂CO₃ (80mL). A pale yellow precipitate was formed which was separated byfiltration. The precipitate was washed thoroughly with water and driedunder vacuum to give the first intermediate compound as a pale yellowshiny solid (7.43 g, 38.18 mmol, 93% over 2 steps). mp 259-261° C.; MS:ES⁺ 194.78, 196.64 (Exact Mass: 194.02).

A second intermediate compound,2-Benzyloxy-7-chloro-3-methyl-[1,8]naphthyridine, was produced asfollows: To a mixture of 7-chloro-3-methyl-1H-[1,8]naphthyridin-2-one(0.30 g, 1.54 mmol, 1.0 equiv) and silver carbonate (0.30 g, 1.08 mmol,0.7 equiv) in toluene (10 mL) was added benzyl bromide (257 μL, 2.156mmol, 1.4 equiv). The reaction was stirred at 60° C. overnight. TLC (50%EtOAc in hexanes) indicated the completion of the reaction. The reactionmixture was filtered through Celite and rinsed thoroughly with tolueneand CH₂Cl₂. The combined filtrates were concentrated under reducedpressure and hexane (20-30 mL) was added to the residue. A whiteprecipitate formed which was collected by filtration and washed withhexane until all the yellow color was washed out. The secondintermediate compound was obtained as a white solid (0.24 g, 56%). m.p.133° C.; MS: ES⁺ 284.90, 286.56 (Exact Mass: 284.07).

A third intermediate compound,2-Benzyloxy-7-(4-benzyloxy-butoxy)-3-methyl-[1,8]naphthyridine, wasproduced ad follows: To a solution of 4-benzyloxy-1-butanol (0.254 g,1.4 mmol, 2.0 equiv) in anhydrous THF (5.0 mL) cooled to −40° C. wasadded potassium tert-butoxide (0.158 g, 1.4 mmol, 2.0 equiv) and themixture was stirred for 10 min. A solution of2-benzyloxy-7-chloro-3-methyl-[1,8]naphthyridine (0.20 g, 0.70 mmol, 1.0equiv) in anhydrous THF (5.0 mL) was added and the reaction mixture wasallowed to warm to RT. The reaction mixture was stirred for 10 min atroom temperature and quenched with water (5.0 mL). The organic phase wasseparated and the aqueous phase was extracted with ethyl acetate (2×10mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated in vacuo to give a yellow oily residue which was purifiedby column chromatography (silica gel, hexane:EtOAc, 8:1) to afford thethird intermediate compound as a pale yellow oil (0.160 g, 55%). MS: ES⁺428.98 (Exact Mass: 428.21).

A fourth intermediate compound,7-(4-Hydroxy-butoxy)-3-methyl-1H-[1,8]naphthyridin-2-one, was producedas follows: To a solution of2-benzyloxy-7-(4-benzyloxy-butoxy)-3-methyl-[1,8]naphthyridine (1.0 g,4.2 mmol) in methanol (200 mL) and THF (20 mL) was added 5% Pd/C (0.3 g)and the mixture was hydrogenated at 35 psi for 4 hours. The slurry wasfiltered through a pad of Celite, rinsed with methanol and the filtratewas concentrated in vacuo to provide the fourth intermediate compound asa white solid (0.58 g, 98%). ¹HNMR was very clean so the product wasused in the next step without further purification. MS: ES⁺ 249.03(Exact Mass: 248.12).

A fifth intermediate compound,4-(6-Methyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyd,was produced as follows: A mixture of pyridinium chlorochromate (PCC)(1.195 g, 5.5 mmol, 2.5 equiv) and neutral alumina (4.2 g, 3.5 g/1.0 gof PCC) in anhydrous CH₂Cl₂ (20 mL) was stirred for 30 min at RT. Asolution of 7-(4-hydroxy-butoxy)-3-methyl-1H-[1,8]naphthyridin-2-one(0.55 g, 2.22 mmol, 1.0 equiv) in CH₂Cl₂ (20 mL) and THF (5 mL) wasadded to the reaction mixture and stirred for 2 h. The reaction mixturewas filtered through a pad of silica and rinsed with CH₂Cl₂ and then 5%MeOH/CH₂Cl₂. The combined filtrates were concentrated in vacuo to givethe fifth intermediate compound as a dark brown oil (0.65 g) which wasused without purification in the next reaction.

To a solution of crude4-(6-methyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(0.65 g, 2.24 mmol, 1.0 equiv) in anhydrous methanol (40 mL) cooled to0° C. was added 2,3-dichlorophenylpiperazine (1.2 g, 4.0 mmol, 2.0equiv). The mixture was stirred for 5 min and NaBH(OAc)₃ (2.3 g, 11.2mmol, 5.0 equiv) was added. The reaction mixture was brought to roomtemperature and stirred overnight. The reaction was quenched with waterand was concentrated to remove methanol completely. The resultant palegreen residue was dissolved in ethyl acetate and washed with 0.5 N HCl(1×10 mL), saturated NaHCO₃ solution (1×10 mL) and brine. The organiclayer was dried over Na₂SO₄ and concentrated. The residue was purifiedby column chromatography (silica gel, 2% MeOH/CH₂Cl₂) to afford thetitle compound as a white foamy solid (0.2 g, 30%). MS: ES⁺ 461.03,463.03 (Exact Mass: 460.14).

EXAMPLE D5 Synthesis of7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3-methyl-1H-[1,8]naphthyridin-2-one

A first intermediate compound,7-(5-Chloro-pent-1-enyl)-3-methyl-1H-[1,8]naphthyridin-2-one, wasproduced as follows: To a solution of compound7-chloro-3-methyl-1H-[1,8]naphthyridin-2-one (0.75 g, 4.11 mmol, 1.0equiv) in anhydrous dioxane (60 mL) were added5-chloro-1-pentenylboronic acid (0.92 g, 6.17 mmol, 1.5 equiv), K₂CO₃(5.70 g, 41.1 mmol, 10.0 equiv) followed by Pd(PPh₃)₄ (0.19 g, 0.16mmol, 0.04 equiv). The mixture was refluxed for 48 h, cooled andfiltered through a small celite bed. The filtrate was concentrated togive a pale yellow residue. Purification by column chromatography onsilica gel (EtOAc:Hexanes:MeOH, 1:1:0.2) gave the first intermediatecompound as a pale yellow solid (0.70 g, 79%). mp: 128-129° C.; ¹HNMR(CDCl₃, 400 MHz): δ 9.22 (br s,1H), 7.75 (d, 1H), 7.50 (s, 1H), 7.10 (d,1H), 6.90-6.80 (m, 1H), 6.55 (dd, 1H), 3.60 (t, 2H), 2.55-2.45 (m, 2H),2.25 (s, 3H), 2.10-1.90 (m, 2H); MS: ES⁺: 263.05 (M+H)⁺, 265.06, (Exactmass: 262.09)

A second intermediate compound,7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3-methyl-1H-[1,8]naphthyridin-2-one,was produced as follows: Kl (0.30 g, 1.79 mmol, 1.0 equiv) was added toa stirred solution of7-(5-chloro-pent-1-enyl)-3-methyl-1H-[1,8]naphthyridin-2-one (0.47 g,1.79 mmol, 1.0 equiv) in CH₃CN (25 mL) and stirred for 1 h.Triethylamine (1 mL), 1-(2,3-dichlorophenyl)piperazine monohydrochloride(0.47 g, 1.79 mmol, 1.0 equiv) and K₂CO₃ (1.0 g, 7.16 mmol, 4.0 equiv)were added and the mixture was refluxed for 48 h. The reaction mixturewas cooled to room temperature and filtered. The solids were washed withEtOAc (5 mL). The filtrate was diluted with EtOAc (20 mL) and washedwith water (20 mL), saturated NaHCO₃ (10 mL) and brine. The organiclayer was dried over Na₂SO₄ and concentrated. Purification of theresidue by column chromatography on silica (EtOAc:Hexanes:MeOH, 4:4:0.5to 1:1:0.5) gave the second intermediate compound as a pale yellow solid(0.28 g, 34%). mp: 82-84° C.; ¹HNMR (400 MHz, CDCl₃) δ 9.40 (br s, 1H),7.75 (d, 1H), 7.55 (s, 1H), 7.20-7.10 (m, 3H), 6.90-6.88 (m, 2H), 6.50(dd, 1H), 3.10 (br s, 4H), 2.75 (br s, 4H), 2.52-2.50 (m, 2H), 2.32-2.28(m, 2H), 2.20 (s, 3H), 1.72-1.68 (m, 2H); MS: ES+ : 457.01 (M+H)⁺,459.00. (Exact mass: 456.15).

A solution of7-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3-methyl-1H-[1,8]naphthyridin-2-one(0.43 g, 0.94 mmol) in THF was added to a slurry of Raney Ni in EtOH.The mixture was hydrogentated for 4 h at 40 psi. The reaction mixturewas filtered through a small celite bed and rinsed with CH₂Cl₂ andmMeOH. The filtrate was concentrated and purified by columnchromatography on silica (10% MeOH/EtOAc) to afford the title compoundas a pale yellow solid (0.22 g, 51.4%). mp: 157-158° C.; ¹HNMR (400 MHz,CDCl₃) δ 9.00 (br s,1H), 7.75 (d,1H), 7.50 (s, 1H), 7.15 (m, 2H),7.00-6.90 (m, 2H), 3.10 (br s, 4H), 2.80 (t, 2H), 2.60 (br s, 4H),2.42-2.38 (m, 2H), 2.20 (s, 3H), 1.82-1.80 (m, 2H), 1.70-1.60 (m, 4H);MS: ES+ : 459.01 (M+H)⁺, 460.97 (Exact mass: 458.16).

EXAMPLE D6a and D6b Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,7-(4-Hydroxy-butoxy)-3-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: A mixture of2-benzyloxy-7-(4-benzyloxy-butoxy)-3-methyl-[1,8]naphthyridine (1.8 g,4.2 mmol) and 5% Pd/C (0.5 g) in methanol (250 mL) was hydrogenatedovernight at 35 psi. The slurry was filtered through a pad of Celitewashing with methanol and the filtrate was concentrated in vacuo toprovide a mixture of7-(4-hydroxy-butoxy)-3-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one and7-(4-hydroxy-butoxy)-3-methyl-1H-[1,8]naphthyridin-2-one as a colorlessviscous material (0.9 g). The products were separated by columnchromatography (silica gel, 5% methano/CH₂Cl₂) to afford the firstintermediate compound (0.45 g, 1.80 mmol, 43%) as a viscous material and7-(4-hydroxy-butoxy)-3-methyl-1H-[1,8]naphthyridin-2-one (0.28 g) as awhite powder. The combined yield was 73%. MS: ES⁺ 251.15 (Exact Mass:250.13).

A second intermediate compound,4-(6-Methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde,was produced as follows: A mixture of pyridinium chlorochromate (PCC)(0.13 g, 0.6 mmol, 2.5 equiv) and neutral alumina (0.45 g, 3.5 g/1.0 gof PCC) in anhydrous CH₂Cl₂ (5.0 mL) was stirred for 30 min at RT. Asolution of7-(4-hydroxy-butoxy)-3-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.06 g, 0.24 mmol, 1.0 equiv) in CH₂Cl₂ (5.0 mL) and THF (2.0 mL) wasadded to the reaction mixture and stirred for 2.0 h. The reactionmixture was filtered through a pad of silica and rinsed with CH₂Cl₂. Thecombined filtrates were concentrated in vacuo to give the secondintermediate compound as a pale yellow oil. The crude (0.05 g) was usedin the next step without purification.

To a solution of crude4-(6-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(0.5 g, 2.0 mmol, 1.0 equiv) in anhydrous methanol (40 mL) cooled to 0°C. was added 2,3-dichlorophenylpiperazine (1.1 g, 4.0 mmol, 2.0 equiv).The mixture was stirred for 5 min and NaBH(OAc)₃ (2.14 g, 10.0 mmol, 5.0equiv) was added. The reaction mixture was brought to room temperatureand stirred overnight. TLC indicated a trace amount of aldehyde wasstill left. More NaBH(OAc)₃ was added and stirring continued for onemore hour. TLC indicated the reaction was complete. The reaction mixturewas concentrated to dryness. The resultant pale green residue wasdissolved in ethyl acetate and washed with 0.5 N HCl (1×10 mL),saturated NaHCO₃ solution (1×10 mL) and brine. The organic layer wasdried over Na₂SO₄ and concentrated. The residue was purified by columnchromatography (silica gel, 2% MeOH/CH₂Cl₂) to afford the title compoundas a colorless viscous material (0.63 g, 75% over 2 steps). Theenantiomers were separated by chiral HPLC (Chiralpak AD, 40:60Hexane/EtOH) to give the enantiomers D6a and D6b. MS: APCl: M+1: 463.1(Exact Mass: 462.16).

EXAMPLE D7 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dimethyl-1H-[1,8]naphthyridin-2-one

A first intermediate compound,7-Chloro-3,4-dimethyl-1H-[1,8]naphthyridin-2-one, was produced asfollows: To a stirred solution of diisopropylamine (0.60 g, 0.83 mL, 5.9mmol) in Et₂O (15 mL) at −78° C. is added n-butyl lithium (2.4 mL, 2.5 Min hexanes, 5.9 mmol). The mixture is stirred at −78° C. for 30 minutesand t-butyl propionate (0.77 g, 0.89 mL, 5.9 mmol) is added dropwise.The mixture is stirred at −78° C. for 30 minutes andN-(3-acetyl-6-chloro-pyridin-2-yl)-2,2-dimethyl-propionamide (0.50 g,1.9 mmol) in Et₂O (3 mL) is added dropwise. A yellow precipitate formsand the mixture is stirred at −78° C. for 30 minutes and warmed to roomtemperature over 3 hours. Water (10 mL) is added, the mixture stirredfor 5 minutes and then diluted with ethyl acetate (20 mL) and brine (10mL). The organic layer is separated, washed with brine (2×20 mL), driedover Na₂SO₄, filtered and concentrated under vacuum. The crude oil isrecrystallized from hexanes to yield3-[6-chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2-methyl-butyricacid tert-butyl ester (0.48 g, 64%). mp 146-148° C., ¹H NMR (200 MHz,CDCl₃) δ 10.50 (br s, 1H), 7.50 (d, 1H), 6.95 (d, 1H), 5.30 (s, 1H),3.10 (q, 1H), 1.48 (s, 3H), 1.45 (s, 9H), 1.30 (s, 9H), 1.22 (d, 3H), MSES+ 384.82 (M⁺).

Aqueous 3 N HCl (20 mL) is added to3-[6-chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2-methyl-butyricacid tert-butyl ester (4.5 g, 15.8 mmol) in dioxane (20 mL). The mixtureis refluxed for 4 hours, cooled to RT, and poured over ice. Theresulting precipitate is filtered, washed with water (2×20 mL) and driedto afford the first intermediate compound (2.4 g, 96%). mp 239-241° C.,¹H NMR (200 MHz, CDCl₃) δ 10.0 (br s, 1H), 7.95 (d, 1H), 7.20 (d, 1H),2.45 (s, 3H), 2.30 (s, 3H), MS ES+ 208.99 (M+H)⁺ (Exact Mass: 208.04).

A second intermediate compound,2-Benzyloxy-7-chloro-3,4-dimethyl-[1,8]naphthyridine, was produced asfollows: 7-Chloro-3,4-dimethyl-1H-[1,8]naphthyridin-2-one (0.20 g, 0.96mmol) in toluene (10 mL) is treated with silver carbonate (0.20 g, 0.73mmol) followed by benzyl bromide (0.25 g, 0.17 mL, 1.4 mmol). Themixture is stirred at 60° C. for 16 hours. The mixture is cooled to RT,filtered and concentrated under vacuum. The crude oil is recrystallizedfrom hexanes to give the second intermediate compound (87 mg, 30%). mp140-141° C., ¹H NMR (400 MHz, CDCl₃) δ 8.20 (d, 1H), 7.55 (d, 1H),7.42-7.30 (m, 5 H), 5.62 (s, 2H), 2.58 (s, 3H), 2.40 (s, 3H), MS ES+299.04 (M+H)⁺ (Exact Mass: 298.09).

A third intermediate compound,2-Benzyloxy-7-(4-benzyloxy-butoxy)-3,4-dimethyl-[1,8]naphthyridine, wasproduced as follows: To a stirred solution of 4-benzyloxy-1-butanol (500mg, 0.49 mL, 2.77 mmol) in THF (6 mL) at −45° C. is added potassiumtert-butoxide (311 mg, 2.77 mmol). The mixture is stirred at −45° C. for10 minutes and then 2-benzyloxy-7-chloro-3,4-dimethyl-[1,8]naphthyridine(661 mg, 2.31 mmol) in THF (5 mL) is added. The solution turns a reddishcolor and is allowed to warm to room temperature over 2 hours. SaturatedNH₄Cl (3 mL) is added and the solution is diluted with ethyl acetate (20mL) and washed with water (20 mL), brine (20 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The crude oil is purified bycolumn chromatography (2:1 hexane/Et₂O) to afford the third intermediatecompound (580 mg, 57%) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 8.10(d, 1H), 7.55-7.50 (m, 2H), 7.40-7.20 (m, 8H), 6.80 (d,1H), 5.60 (s,2H), 4.56 (t, 2H), 4.54 (s, 2H), 3.58 (t, 2H), 2.55 (s, 3H), 2.30 (s,3H), 2.00-1.80 (m, 4H), MS ES+ 442.93 (M⁺) (Exact Mass: 442.23).

A fourth intermediate compound,7-(4-Hydroxy-butoxy)-3,4-dimethyl-1H-[1,8]naphthyridin-2-one, wasproduced as follows: To a solution of2-benzyloxy-7-(4-benzyloxy-butoxy)-3,4-dimethyl-[1,8]naphthyridine (500mg, 1.1 mmol) in MeOH (20 mL) is added 10% Pd/C (200 mg) and the mixtureis shaken under 45 psi H₂ for 3 hours. The mixture is then filteredthrough Celite and concentrated under vacuum to yield the fourthintermediate compound (272 mg, 92%) as a white solid. mp 172-174° C., ¹HNMR (400 MHz, DMSO-d₆) δ 6 11.80 (s, 1H), 8.02 (d, 1H), 6.61 (d, 1H),4.42 (t, 1H), 4.34 (t, 2H), 3.45 (t, 2H), 2.34 (s, 3H), 2.04 (s, 3H),1.80-1.70 (m, 2H), 1.60-1.55 (m, 2H), MS ES+ 263.06 (M+H)⁺ (Exact Mass:262.13).

A fifth intermediate compound,4-(5,6-Dimethyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde,was produced as follows: To a stirred solution of Dess-Martinperiodinane (178 mg, 0.42 mmol) in CH₂Cl₂ (10 mL) at room temperature isadded 7-(4-hydroxy-butoxy)-3,4-dimethyl-1H-[1,8]naphthyridin-2-one (100mg, 0.38 mmol) in THF (6 mL). The resulting mixture is stirred for 1hour and then Et₂O (10 mL) is added. The resulting suspension is pouredinto a mixture of saturated NaHCO₃ (10 mL) and Na₂S₂O₃ (464 mg, 2.94mmol) and stirred for 10 minutes. The organic layer is separated, washedwith saturated NaHCO₃ (10 mL) and brine (10 mL), dried over Na₂SO₄,filtered and concentrated under vacuum. The crude aldehyde is usedwithout purification in the next step.

The crude4-(5,6-dimethyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(100 mg, 0.38 mmol) is dissolved in dichloroethane (7 mL) and1-(2,3-dichlorophenyl)piperazine monohydrochloride (112 mg, 0.42 mmol)is added, followed by triethylamine (39 mg, 0.05 mL, 1.14 mmol). Themixture is stirred for 5 minutes and NaBH(OAc)₃ (81 mg, 0.38 mmol) isadded. The mixture is stirred at room temperature for 1 hour and water(5 mL) is added. The organic layer is separated, washed with brine (10mL), dried over Na₂SO₄, filtered and concentrated under vacuum. Thecrude solid is purified by column chromatography (1:9 methanol/ethylacetate) to yield the title compound (123 mg, 68%) as a white solid. mp161-163 OC, ¹H NMR (400 MHz, CDCl₃) δ 8.98 (br s, 1H), 7.80 (d, 1H),7.20-7.10 (m, 2 H), 7.00-6.90 (m, 1H), 6.60 (d, 1H), 4.20 (t, 2H),3.15-3.00 (m, 4H), 2.75-2.60 (m, 4H), 2.50 (t, 2H), 2.40 (s, 3H), 2.20(s, 3H), 1.85-1.60 (m, 4H), MS ES+ 474.76 (M)⁺ (Exact Mass: 474.16).

EXAMPLE D8 Synthesis of7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dimethyl-1H-[1,8]naphthyridin-2-one

A first intermediate compound,7-(5-Chloro-pent-1-enyl)-3,4-dimethyl-1H-[1,8]naphthyridin-2-one, wasproduced as follows: To a stirred solution of7-chloro-3,4-dimethyl-1H-[1,8]naphthyridin-2-one (2.0 g, 9.6 mmol) indioxane (20 mL) was added Pd(PPh₃)₄ (334 mg, 0.29 mmol) and the mixturewas stirred for 5 min. 5-Chloro-1-pentenyl boronic acid (2.140 g, 14.42mmol) was added followed by aqueous Na₂CO₃ (2 M, 20 mL) and the mixturewas heated at 100° C. for 18 h. The mixture was cooled to roomtemperature and diluted with water (20 mL) and ethyl acetate (30 mL).The organic layer was separated and washed with brine (20 mL), driedover anhydrous Na₂SO₄, filtered and evaporated. The crude solid wasrecrystallized from CH₂Cl₂/hexanes to yield the first intermediatecompound as a light yellow solid (1.12 g, 42%). mp 152-153° C., ¹H NMR(400 MHz, CDC1₃) δ 8.95 (s, 1H), 7.88 (d, 1H), 7.05 (d, 1H), 6.82 (dt,1H), 6.50 (d, 1H), 3.60 (t, 2H), 2.46-2.40 (m, 2H), 2.39 (s, 3H), 2.22(s, 3H), 2.04-1.98 (m, 2H), MS ES+ 277.06 (M+H)⁺.

A second intermediate compound,7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dimethyl-1H-[1,8]naphthyridin-2-one,was produced as follows: To a stirred solution of7-(5-chloro-pent-1-enyl)-3,4-dimethyl-1H-[1,8]naphthyridin-2-one (500mg, 1.81 mmol) in CH₃CN (20 mL) were added 1-(2,3-dichlorophenyl)piperazine monohydrochloride (581 mg, 2.17 mmol), Kl (361 mg, 2.17 mmol)and K₂CO₃ (1.25 g, 9.05 mmol). The mixture was refluxed for 48 h, cooledto room temperature, and diluted with water (10 mL) and CH₂Cl₂ (10 mL).The organic layer was separated, washed with water (10 mL) and brine (10mL), dried over anhydrous Na₂SO₄, filtered and evaporated in vacuo. Thecrude solid was purified by column chromatography (5% MeOH/CH₂Cl₂) toyield the second intermediate compound as a yellow solid (416 mg, 49%).mp 92-97° C., ¹H NMR (400 MHz, CDCl₃) δ 10.00 (br s, 1H), 7.85 (d, 1H),7.10-7.03 (m, 3H), 6.98-6.80 (m, 2H), 6.56 (d, 1H), 3.10-3.00 (m, 4H),2.80-2.60 (m, 4H), 2.50 (t, 2H), 2.40 (s, 3H), 2.38-2.24 (m, 2H), 2.22(s, 3H), 1.82-1.70 (m, 2H), MS ES+ 471.02 (M+H)⁺ (Exact Mass: 470.16).

7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dimethyl-1H-[1,8]naphthyridin-2-one(80 mg, 0.17 mmol) was dissolved in a minimal amount of THF (2 mL) andthe solution was diluted with ethanol (10 mL). The solution was treatedwith Raney Nickel (0.5 mL slurry in water) and shaken under 45 psi H₂for 3 h. The mixture was filtered through celite. The celite pad waswashed with THF (2×10 mL), and the filtrate was evaporated in vacuo. Thecrude solid was purified by column chromatography (5% MeOH/CH₂Cl₂) toyield the title compound as a white solid (64 mg, 80%). mp 202-203° C.,¹H NMR (400 MHz, CDCl₃) δ 8.98 (br s, 1H) 7.84 (d, 1H), 7.20-7.15 (m,2H), 7.04 (d, 1H), 6.98-6.95 (m, 1H), 3.15-3.00 (m, 4H), 2.81 (t, 2H),2.70-2.55 (m, 4H), 2.46-2.36 (m, 5H), 2.22 (s, 3H), 1.82-1.75 (m, 2H),1.60-1.50 (m, 2H), 1.45-1.36 (m, 2H), MS ES+ 473.00 (M+H)⁺ (Exact Mass:472.18).

EXAMPLE D9 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-fluoro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,N-{3-Formyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,2-dimethyl-propionamide,was produced as follows: To a cooled (−78° C.) solution of2,2-dimethyl-N-{6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-propionamide(7.0 g, 20 mmol) in THF was added n-BuLi (20 mL, 2.5 M in Hexane, 50mmol). The mixture was stirred at 0 °° C. for 3.5 h and then cooled backto −78° C. DMF (4.6 mL, 60mmol) was added dropwise with vigorousstirring. The cooling bath was removed and the reaction was allowed towarm to 0° C. The reaction was quenched with saturated aqueous NH₄Cl (20mL) and extracted with EtOAc (300 mL). The organic layer was washed withwater (2×20 mL) and brine (20 mL), dried over Na₂SO₄ and concentrated togive an oil which was purified by column chromatography (20%EtOAc/Hexanes) to give the first intermediate compound as a pale yellowoil (5.8 g, 77%). ¹HNMR (400 MHz, δ ppm): 11.50 (br s, 1H), 9.85 (s,1H), 7.80 (d, 1H), 6.50 (d, 1H), 4.55 (m, 3H), 3.85 (m, 2H), 3.45 (m,2H), 2.00-1.50 (m, 10H), 1.40 (s, 9H).

A second intermediate compound,3-Fluoro-7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one, was producedas follows: To a mixture ofN-{3-formyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,2-dimethyl-propionamide(4.10 g, 10.85 mmol), triethyl-2-fluoro-2-phosphonoacetate (5.30 g,21.70 mmol, 2 eq) and LiCl (0.91 g, 21.70 mmol, 2 eq) in CH₃CN was addedDBU (3.30 g, 21.70 mmol, 2 eq) dropwise at such a rate that thetemperature of the mixture did not exceed 30° C. The mixture was stirredat room temperature overnight and quenched with saturated NH₄Cl (30 mL).The mixture was extracted with EtOAc (200 mL). The organic layer waswashed with water (20 mL) and brine (20 mL), dried over Na₂SO₄ andconcentrated to give a mixture of cis- and trans-α, β-unsaturatedesters. This mixture was dissolved in dioxane (40 mL) and 3 N HCl (20mL) and refluxed for 2 h. The reaction was cooled in an ice-bath andneutralized with K₂CO₃ (pH 8). The mixture was extracted with THF (250mL). The organic layer was washed with brine (30 mL), dried over Na₂SO₄and concentrated. The residue was purified by column chromatography (5%MeO/CH₂Cl₂) to give the second intermediate compound as a pale yellowsolid (700 mg, 26%). ¹HNMR (400 MHz, δ ppm): 7.90 (d, J=8.5 Hz, 1H),7.70 (d, J=8.6 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 4.42 (t, J=6.7 Hz, 2H),3.61 (t, J=6.0 Hz, 2H), 1.90 (m, 2H), 1.70 (m, 2H).

To a suspension of Dess-Martin periodinane (1.09 g, 2.56 mmol, 1.2 eq)in CH₂Cl₂ (30 mL) was added a solution of3-fluoro-7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one (0.538 g, 2.13mmol) in THF (10 mL)/DMSO (2 mL). The mixture was stirred at roomtemperature for 1.5 h. The reaction mixture was diluted with Et₂O (100mL) and quenched with aqueous NaHCO₃ (30 mL) containing Na₂S₂O₃ (2.36 g,14.91 mmol, 7 eq). After extraction with Et₂O (3×50 mL), the combinedorganic layer was washed with brine (20 mL), dried over Na₂SO₄ andconcentrated to give the crude aldehyde as a pale yellow solid. To asolution of the aldehyde in 1,2-dichloroethane (40 mL) was added1-(2,3-dichlorophenyl)piperazine monohydrochloride (0.803 g, 3.0 mmol,1.4 eq), Et₃N (0.54 mL, 4.0 mmol, 1.9 eq), and NaBH(OAc)₃ (0.631g, 3.0mmol, 1.4 eq). The mixture was stirred at room temperature for 1 h andthen quenched with water and saturated NaHCO₃. After extraction withCH₂Cl₂ (3×50 mL), the combined organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by column chromatography (3%MeOH/CH₂Cl₂) to give the title compound (900 mg, 91% in two steps).¹HNMR( 400 MHz, δ ppm): 12.60 (brs, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.80(d, J=8.3 Hz, 1H), 7.30 (m, 2H), 7.10 (m, 1H), 6.75 (d, J=8.5 Hz, 1H),4.40 (t, J=7.0 Hz, 2H), 3.00 (brs, 4H), 2.50 (brs, 4H), 2.40 (t, J=6.5Hz, 2H), 1.80 (m, 2H), 1.60 (m, 2H); ¹⁹FNMR: −140 ppm; MS: 465 (M+H)⁺(Exact Mass: 464.12).

EXAMPLE D10 Synthesis of 3-Fluoro-7-[4-(4-naphthalen-1-vl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

To a suspension of Dess-Martin periodinane (0.79 g, 1.86 mmol, 1.2 eq)in CH₂Cl₂ (20 mL) was added a solution of3-fluoro-7-(4-hydroxy-butoxy)-1H- [1,8]naphthyridin-2-one (0.39 g, 1.5mmol) in THF (6 mL)/DMSO (2 mL). The mixture was stirred at roomtemperature for 1.5 h. The reaction mixture was diluted with Et₂O (100mL) and quenched with aqueous NaHCO₃ (20 mL) containing Na₂S₂O₃ (1.66 g,10.5 mmol, 7 eq). After extraction with Et2O (3×40 mL), the combinedorganic layer was washed with brine (20 mL), dried over Na₂SO₄ andconcentrated to give the crude aldehyde as a pale yellow solid. To asolution of the aldehyde in 1,2-dichloroethane (20 mL) was added1-naphthalen-1-yl-piperazine monohydrochloride (0.522 g, 2.1 mmol, 1.4eq), Et₃N (0.38 mL, 2.85 mmol, 1.9 eq) and NaBH(OAc)₃ (0.445 g, 2.1mmol, 1.4 eq). The mixture was stirred at room temperature for 1 h andquenched with water and saturated NaHCO₃. After extraction with CH₂Cl₂(3×50 mL), the combined organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by column chromatography (3%MeOH/CH₂Cl₂) to give the title compound (430 mg, 62% in two steps).¹HNMR( 400 MHz, δ ppm): 12.60 (br s, 1H), 8.10 (d, J=6.0 Hz, 1H), 8.00(d, J=7.2 Hz, 1H), 7.85 (m, 2H), 7.60 (d, J=6.0 Hz, 1H), 7.50 (m, 2H),7.40 (d, J=6.0 Hz, 1H), 7.10 (d, J=6.0 Hz, 1 H), 6.75 (d, J=7.0 Hz, 1H),4.35 (t, J=4.0 Hz, 2H), 3.00 (br s, 4H), 2.60 (br s, 4H), 2.40 (t, J=3.8Hz, 2H), 1.80 (m, 2H), 1.60 (m, 2H); ¹⁹FNMR: −140 ppm; MS: 447 (M+H)⁺(Exact Mass: 446.21).

EXAMPLE D11 Synthesis of7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3-(2,2,2-trifluoro-ethyl)-1H-[1,8]naphthyridin-2-one

An intermediate compound,7-(4-Hydroxy-butoxy)-3-(2,2,2-trifluoro-ethyl)-1H-[1,8]naphthyridin-2-one,was produced as follows: To a cooled (−78° C.) solution of LiHMDS (47.6mL, 1 M in THF) was added ethyl 4,4,4-trifluorobutyrate (8.10 g, 47.6mmol) dropwise and the mixture was stirred for 1 hour. A solution ofN-{3-formyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,2-dimethyl-propionamide(3.0 g, 7.93 mmol) in THF (15 mL) was added. The cooling bath was thenremoved and the reaction was allowed to gradually warm to 0° C. Thereaction was quenched with aqueous NH₄Cl (30 mL) and the mixture wasextracted with EtOAc. The organic layer was washed with water and brine,dried over Na₂SO₄ and concentrated to give the condensation productwhich was used in the next step without further purification.

The crude material obtained in the last step was dissolved in dioxane(30 mL) and 3 N HCl (15 mL). The resulting solution was refluxedovernight and neutralized with K₂CO₃ (pH 8) while cooling with anice-bath. The mixture was extracted with EtOAc (3×50 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated to give a mixtureof the desired product,7-(4-hydroxy-butoxy)-3-(2,2,2-trifluoro-ethyl)-1H-[1,8]naphthyridin-2-one,and a side-product,2-[2-amino-6-(4-hydroxy-butoxy)-pyridin-3-ylmethylene]-4,4,4-trifluoro-butyricacid ethyl ester. The crude mixture was dissolved in MeOH (20 mL) andwater (10 mL) and KOH (1.07 g) was added. The resulting mixture wasstirred overnight at RT. The mixture was concentrated and the residuewas extracted with EtOAc (3×50 mL). The combined organic layers weredried over Na₂SO₄ and concentrated to give an oil which was purified bychromatography on silica gel (3% MeOH/CH₂Cl₂) to give the intermediatecompound as a yellow solid (260 mg, 10% in three steps). ¹HNMR (400 MHz,δ ppm): 9.78 (br s, 1H), 7.75 (d, J=5.6 Hz, 2H), 6.60 (d, J=5.6 Hz),4.70 (t, J=3.4 Hz), 4.50 (t, J=3.6 Hz), 3.80 (m, 2H), 3.50 (q, J=7 Hz,2H), 1.60-2.00 (m, 4H). ¹⁹FNMR: −65 ppm, MS: 317 (M⁺).

To a suspension of Dess-Martin periodinane (0.419 g, 0.99 mmol, 1.2 eq)in CH₂Cl₂ (20 mL) was added a solution of7-(4-hydroxy-butoxy)-3-(2,2,2-trifluoro-ethyl)-1H-[1,8]naphthyridin-2-one(0.26 g, .82 mmol) in THF (8 mL ). The mixture was stirred at roomtemperature for 1 h. Et₂O (100 mL) was added to dilute the reactionmixture. The reaction was quenched with aqueous NaHCO₃ (20 mL)containing Na₂S₂O₃ (0.91 g, 5.74 mmol, 7 eq). After extraction with Et₂O(3×50 mL), the combined organic layer was washed with brine (20 mL),dried over Na₂SO₄, and concentrated to give the crude aldehyde as a paleyellow solid. To a solution of the crude aldehyde in 1,2-dichloroethane(20 mL) was added 1-naphthalen-1-yl-piperazine monohydrochloride (0.286g, 1.15 mmol, 1.4 eq), Et₃N (0.21 mL, 1.56 mmol, 1.9 eq) and NaBH(OAc)₃(0.241 g, 1.15 mmol, 1.4 eq). The mixture was stirred at roomtemperature for 1 h. The reaction was quenched with water and saturatedNaHCO₃. After extraction with CH₂Cl₂ (3×50 mL), the combined organiclayer was dried over Na₂SO₄ and concentrated. The residue was purifiedby column chromatography (2% MeOH/CH₂Cl₂) to give the title compound(200 mg, 50% in two steps). ¹HNMR (400 MHz, δ ppm): 9.05 (br s, 1H),8.20 (d, J=6.2 Hz, 1H), 7.80 (d, J=6.0 Hz 1H), 7.75 (m, 2H), 7.58 (d,J=6.3 Hz, 1H), 7.50 (m, 2H), 7.40 (t, J=6.3 Hz, 1H), 7.10 (d, J=5.3 Hz,1H), 6.40 (d, J=6.5 Hz, 1H), 4.40 (t, J=4.2 Hz, 2H), 3.50 (q, J=7.5 Hz,2H), 3.20 (br s, 4H), 2.80 (br s, 4H), 2.60 (m, 2H), 1.90 (m, 2H), 1.72(m, 2H). ¹⁹FNMR: −65.6 ppm. MS: 511 (M⁺). Elemental Analysis calculatedfor C₂₈H₂₉F₃N₄O₂: C, 65.88; H, 5.69; N, 10.98. Found: C, 66.08; H, 5.89;N, 10.67.

EXAMPLE D12 Synthesis of7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,3-[6-Chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2,2-dimethyl-propionicacid methyl ester, was produced as follows: To a stirred solution ofoxalyl chloride (11.0 g, 87.0 mmol) in CH₂Cl₂ (180 mL) at −60° C. wasadded a solution of DMSO (12.9 mL, 182 mmol) in CH₂Cl₂ (40 mL), dropwiseat a rapid rate. The resulting solution was stirred for 5 min, then asolution of methyl-2,2-dimethyl-3-hydroxypropionate (10.0 g, 75.6 mmol)in CH₂Cl₂ (10 mL) was added dropwise over 10 min. The cloudy mixture wasthen stirred for 15 min, at which time triethylamine (52 mL, 380 mmol)was added dropwise, maintaining the temperature at or below −50° C.After stirring for 5 min, the mixture was allowed to warm to roomtemperature and water (200 mL) was then added. The layers were separatedand the aqueous layer extracted with CH₂Cl₂ (2×100 mL). The combinedorganic layers were washed successively with 1 M HCl (100 mL), water(100 mL), saturated NaHCO₃ solution (100 mL), water (100 mL) and brine(100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo untilonly a small volume of CH₂Cl₂ remained, to minimize the loss of thevolatile product. The crude product was purified by vacuum distillationaffording the desired product 2,2-dimethyl-3-oxopropionic acid methylester (8.1 g, 83%, 89° C., ca 80 mmHg). ¹H NMR (CDCl₃) δ 9.67 (s,1H),3.76 (s, 3H), 1.36 (s, 6H).

To a stirred solution ofN-(6-chloro-pyridin-2-yl)-2,2-dimethyl-propionamide (12.0 g, 56.6 mmol)in THF (180 mL) at −78° C., was added dropwise, n-butyllithium (95.0 mL,153 mmol, 1.6 M in hexanes). After the addition was complete, themixture was warmed to −20° C. and stirred at this temperature for 3 h.The reaction mixture was then cooled to −78° C. and added, via cannula,to a stirred solution of 2,2-dimethyl-3-oxopropionic acid methyl ester(14.7 g, 130 mmol) in THF (50 mL) at −78° C. After stirring for 2 h, thereaction was quenched by the addition of a saturated NH₄Cl solution,diluted with ethyl acetate (50 mL) and warmed to RT. The organic layerwas removed and washed with water (50 mL), saturated NaHCO₃ (50 mL),water (50 mL) and brine (50 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by silica gelchromatography (90:10 to 50:50 hexanes/ethyl acetate) to afford thefirst intermediate compound (10.7 g, 55%) as a pale yellow solid. 1 HNMR (CDCl₃) δ 8.77 (br s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.13 (d, J=8.1Hz, 1H), 5.06 (d, J=3.8 Hz, 1H), 3.70 (s, 3H), 3.61 (d, J=3.9 Hz, 1 H),1.33 (s, 9H), 1.24 (s, 3H), 1.21 (s, 3H); MS (ESI) m/z 343[C₁₆H₂₃ClN₂O₄+H]⁺.

A second intermediate compound,7-Chloro-4-hydroxy-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows:3-[6-Chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2,2-dimethyl-propionicacid methyl ester (2.0 g, 5.8 mmol) was partially dissolved in a mixtureof 3M HCl and dioxane (1:1, 120 mL). The mixture was refluxed for 90min, cooled to room temperature and concentrated in vacuo. The residuewas partitioned between ethyl acetate (100 mL) and a saturated NaHCO₃solution (100 mL). The aqueous layer was removed and extracted withethyl acetate (2×30 mL). The combined organic layers were washed withbrine (50 mL), dried over Na₂SO₄, filtered and concentrated. The cruderesidue was purified by silica gel chromatography (80:20 to 40:60hexanes/ethyl acetate) to afford the second intermediate compound (0.85g, 65%) as a pale yellow foamy solid. ¹H NMR (CDCl₃) δ 7.78 (br s, 1H),7.69 (d, J=7.7 Hz, 1H), 7.04 (d, J=7.7 Hz, 1H), 4.53 (d, J=4.7 Hz,1H),2.12 (d, J=5.0 Hz,1H), 1.26 (s, 3H), 1.23 (s, 3H); MS (ESI) m/z 227[C₁₀H₁₁ClN₂O₂+H]⁺; Anal. Calcd for C₁₀H₁₁ClN₂O₂: C, 52.99; H, 4.89; N,12.36; Cl, 15.64. Found: C, 53.17; H, 4.88; N, 12.27; Cl, 15.63.

A third intermediate compound,7-Chloro-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one, wasproduced as follows: To a solution of7-chloro-4-hydroxy-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.71 g, 3.14 mmol) in TFA (10 mL) was added triethylsilane (1.5 mL, 9.7mmol, 3.1 equiv). The mixture was heated at reflux for 2 h. The reactionwas cooled to room temperature and concentrated. The residue wasdissolved in CH₂Cl₂, washed with saturated NaHCO₃ and brine, andconcentrated to give a solid. The solid was triturated with hexanes andfiltered to give the third intermediate compound (520 mg, 80%). MS: ESI:m/z: 210.98 (Exact Mass: 210.06).

A fourth intermediate compound,7-(5-Chloro-pent-1-enyl)-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: A 100 mL round bottom flask was charged with7-chloro-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one (520 mg,2.47 mmol), 5-chloro-pent-1-enyl-boronic acid (769 mg, 5.2 mmol),Pd(PPh₃)₄ (0.14 g, 0.12 mmol, 5 mol %) and Na₂CO₃ (262 mg, 2.47 mmol).DME (20 mL) and H₂O (5 mL) were added and the reaction was heated atreflux for 11 h. The reaction was cooled to room temperature and stirredovernight. The solvents were evaporated and the residue was partitionedbetween EtOAc (50 mL) and H₂O (50 mL). The organic layer was washed withH₂O, saturated NaHCO₃ and brine, dried over Na₂SO₄ and concentrated.Purification by liquid chromatography (SiO₂, 5 to 35% EtOAc/Hexanes)afforded the fourth intermediate compound (560 mg, 82%). MS: ESI: m/z:279.12 (Exact Mass: 278.12).

A fifth intermediate compound,7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: To a solution of7-(5-chloro-pent-1-enyl)-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.55 g, 1.98 mmol) in CH₃CN (50 mL) was added1-(2,3-dichloro-phenyl)-piperazine (0.63 g, 2.37 mmol), K₂CO₃ (0.87 g,6.34 mmol) and Nal (0.35 g, 2.37 mmol). The mixture was heated at refluxfor 3 days. The reaction mixture was poured into H₂O and extracted withCH₂Cl₂. The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated. Purification by liquid chromatography (Biotage 25M, CH₂Cl₂to 5% MeOH/CH₂Cl₂) gave the product contaminated with a small amount ofstarting chloro compound. Repurification by liquid chromatography(Biotage 25M, EtOAc to 5% MeOH/EtOAc) afforded the pure fifthintermediate compound (640 mg, 68%). MS: ESI: ml/z: 473.34 (Exact Mass:472.18).

A Parr shaker was charged with PtO2 (0.12 g) and EtOAc (25 mL) was addedunder N₂. The catalyst was shaken under a H₂ atmosphere (50 psi) for 10min and a suspension of7-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.54 g, 1.15 mmol) in EtOAc (125 mL) was added. The mixture was shakenunder H₂ (50 psi) for 1.5 h. The reaction was filtered through Celitewashing with MeOH and the filtrate was concentrated to give an oilyresidue. Hexanes was added and the mixture was concentrated to give thetitle compound as a white solid (0.54 g, 99%). MS: ESI: m/z: 475.32(Exact Mass: 474.20).

EXAMPLE D13 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, 7-Chloro-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione, was produced as follows: Toa suspension of Dess Martin periodinane (5.61 g, 13.23 mmmol) in CH₂Cl₂(25 mL) was added a solution of 7-chloro-4-hydroxy-3, 3-dimethyl-3,4-dihydro-1H-[1,8] naphthyridin-2-one (2.0 g, 8.82 mmol) in CH₂Cl₂/THF(40 mL/10 mL) via cannula. The reaction was stirred at room temperaturefor 2 hours. Upon completion, a 1:1 mixture of saturated Na₂S₂O₃ andsaturated NaHCO₃ (75ml) were added, followed by Et₂O. The mixture wasstirred for 20 minutes, and then extracted with a mixture of EtOAc/Et₂O(1:2). The organic layer was washed with saturated NaHCO₃ and brine,dried over Na₂SO₄ and concentrated to give the first intermediatecompound as a pale yellow solid (1.96 g, 98%). MS: APCl: M+1: 225.1(Exact Mass: 224.04).

A second intermediate compound,7-(4-Benzyloxy-butoxy)-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione, wasproduced as follows: To a solution of 4-benzyloxy-butan-1-ol (4.7 mL,26.70 mmol) in dry THF was added KO^(t)Bu (1M in THF, 25.3 mL, 25.34mmol). The mixture was stirred for 20 minutes and then added to asolution of 7-chloro-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione (1.5g, 6.67 mmol) in dry THF. The reaction was stirred at room temperaturefor 1 hour. The reaction was quenched with saturated NH₄Cl andpartitioned between water and EtOAc. The organic layer was washed withsaturated NaHCO₃ and brine, dried over Na₂SO₄ and concentrated.Purification by liquid chromatography on silica gel (10-40%EtOAc/Hexanes) gave the second intermediate compound as a colorless oil(2.25 g, 91%). MS: APCl: M+1: 369.5 (Exact Mass: 368.17).

A third intermediate compound,7-(4-Hydroxy-butoxy)-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows:7-(4-Benzyloxy-butoxy)-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione(2.26 g, 6.13 mmol) was hydrogenated using 20% Pd/C (0.25 g) in THF for1 h. A mixture of the title compound and4-hydroxy-7-(4-hydroxy-butoxy)-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one was obtained. The mixture wasfiltered and concentrated to give an oil. Purification by liquidchromatography on silica gel (50-100% EtOAc/Hexanes) gave the thirdintermediate compound (0.321 g, 19%). MS: APCl: M+1: 265.1 (Exact Mass:264.15).

A fourth intermediate compound, 4-(6,6-Dimethyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde, was producedas follows: To a suspension of Dess Martin periodinane (0.693 g, 1.63mmol) in dry CH₂Cl₂ (5 mL) was added a solution of7-(4-hydroxy-butoxy)-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.287 g, 1.08 mmol) in dry CH₂Cl₂ (5 mL) via cannula. The reaction wasstirred at room temperature for 7 hours. A 1:1 mixture of saturatedNaHCO₃ and saturated Na₂S₂O₃ was added (30 mL), followed by Et₂O. Themixture was stirred for 15 minutes and then extracted with Et₂O/EtOAc.The organic layer was washed with saturated NaHCO₃ and brine, dried overNa₂SO₄ and concentrated to afford the fourth intermediate compound as awhite solid (0.268 g, 1.02 mmol, 94%). MS: APCl: M−1: 261.0 (Exact Mass:262.13).

To a solution of4-(6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(0.250 g, 0.953 mmol) in DCE (6 mL) was added1-(2,3-dichloro-phenyl)-piperazine hydrochloride (0.255 g, 0.953 mmol)followed by Et₃N (0.27 mL, 1.90 mmol). The mixture was stirred for 20minutes at room temperature and NaBH(OAc)₃ (0.282 g, 1.33 mmol) wasadded. The reaction was stirred for 2.5 h and quenched with saturatedNaHCO₃ and water. The mixture was extracted with EtOAc and the organiclayer was washed with saturated NaHCO₃, water and brine, dried overNa₂SO₄ and concentrated. Purification by liquid chromatography on silicagel (0-5% MeOH/CH₂Cl₂) gave a foam (0.214 g, 0.443 mmol, 46%). The foamwas dissolved in Et₂O and treated with maleic acid to give a whitesolid. MS: APCl: M+1: 477.1 (Exact Mass: 476.17).

EXAMPLE D14 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione

A first intermediate compound,3,3-Dimethyl-7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-1H-[1,8]naphthyridine-2,4-dione,was produced as follows: To a solution of4-(tetrahydro-pyran-2-yloxy)-butan-1-ol (1.93 g, 11.07 mmol) in dry THF(4 mL) was added KO^(t)Bu (1M in THF, 10.5 mL, 10.5 mmol). The mixturewas stirred for 20 minutes and then added to a solution of7-chloro-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione (0.621 g, 2.76mmol) in dry THF (5 mL). The reaction was stirred at room temperaturefor 1 hour. The reaction was quenched with saturated NH₄Cl andpartitioned between water and EtOAc. The organic layer was washed withsaturated NaHCO₃ and brine, dried over Na₂SO₄ and concentrated.Purification by liquid chromatography on silica gel (10-40%EtOAc/Hexanes) gave the first intermediate compound as an orange oil(0.89 g, 2.40 mmol, 88%). MS: APCl: M+1: 363.1 (Exact Mass: 362.18).

A second intermediate compound,7-(4-Hydroxy-butoxy)-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione, wasproduced as follows: To a solution of3,3-dimethyl-7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-1H-[1,8]naphthyridine-2,4-dione(1.22 g, 3.37 mmol) in EtOH (15 mL) was added PPTS. The reaction washeated to 60° C. for 3 hours. The reaction was cooled and concentratedto give an oil. Purification by liquid chromatography on silica gel(30-70% EtOAc/Hexanes) gave the second intermediate compound as a whitesolid (0.373 g, 40%). MS: APCl: M+1: 279.1 (Exact Mass: 278.13).

A third intermediate compound,4-(6,6-Dimethyl-5,7-dioxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde,was produced as follows: To a suspension of Dess Martin periodinane(2.256 g, 5.31 mmol) in dry CH₂Cl₂ (5 mL) was added a solution of7-(4-hydroxy-butoxy)-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione (0.37g, 1.30 mmol) in dry CH₂Cl₂ (5 mL) via cannula. The reaction was stirredat room temperature for 4 hours. A 1:1 mixture of saturated NaHCO₃ andsaturated Na₂S₂O₃ was added (40 mL), followed by Et₂O. The mixture wasstirred for 15 minutes and then extracted with Et₂O/EtOAc. The organiclayer was washed with saturated NaHCO₃ and brine, dried over Na₂SO₄ andconcentrated to afford the third intermediate compound as a yellow film(0.52 g, 1.22 mmol, 65%). MS: APCl: M+1: 277.1 (Exact Mass: 276.11).

To a solution of4-(6,6-dimethyl-5,7-dioxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(0.520 g, 1.88 mmol) in DCE (6 mL) was added1-(2,3-dichloro-phenyl)-piperazine hydrochloride (0.503 g, 1.88 mmol)followed by Et₃N (0.53 mL, 3.76 mmol). The mixture was stirred for 20minutes at room temperature and NaBH(OAc)₃ (0.56 g, 2.60 mmol) wasadded. The reaction was stirred for 2.5 h and quenched with saturatedNaHCO₃ and water. The mixture was extracted with EtOAc and the organiclayer was washed with saturated NaHCO₃, water and brine, dried overNa₂SO₄ and concentrated. Purification by liquid chromatography on silicagel (0-5% MeOH/CH₂Cl₂) gave a white solid (0.277 g, 0.564 mmol, 30%).MS: APCl: M+1: 491.1 (Exact Mass: 490.15).

EXAMPLE D15 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4-hydroxy-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

To a solution of7-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione(0.132 g, 0.268 mmol) in THF (2 mL), cooled to 0° C. was added NaBH₄(0.013 g, 0.335 mmol). The reaction was warmed to room temperature andstirred for 3 hours. The reaction was quenched with saturated NaHCO₃ andpartitioned between EtOAc and water. The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated to give the title compound asa white solid (0.095 g, 0.192 mmol, 57%). MS: APCl: M+1: 493.1 (ExactMass: 492.17).

EXAMPLE D16 Synthesis of4,4-Dimethyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, 3-Methyl-but-3-enoic acid(6-amino-pyridin-2-yl)-amide, was produced as follows:2,5-Diaminopyridine (70 g, 0.641 mol) was dissolved in 2100 mL THF in a5 L 4-neck flask equipped with mechanical stirring, N₂ line and a 500 mLaddition funnel. Et₃N (447 mL, 5 eq.) was added to the reaction flask.3,3-Dimethylacryloyl chloride (76 g, 0.641 mol) was diluted with 700 mLTHF and this solution was added dropwise to the reaction flask. Themoderate exotherm observed was controlled with an ice/water bath tomaintain a temperature <15° C. After the addition was complete, thereaction was allowed to warm to room temperature and stirred under N₂for 1.5 h. The reaction mixture was concentrated and CH₂Cl₂ was added.The CH₂Cl₂ solution was washed with H₂O and the aqueous layer was backextracted with CH₂Cl₂. The organic layers were combined and dried overNa₂SO₄, filtered and concentrated to an oil. The crude product waspurified by column chromatography using a gradient mobile phase of10%-30% EtOAc in hexanes. All fractions containing the desired productwere pooled and concentrated to an oil. NMR analysis of the productindicated the product was a 1:1 mixture of 2 isomers, the alpha betaunsaturated and the beta gamma unsaturated isomer resulting in firstintermediate compound (90.0 g, 0.47 mol, 73%). MS: APCl: M+1: 192.0(Exact Mass: 191.11).

A second intermediate compound,7-Amino-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one, wasproduced as follows: 3-Methyl-but-3-enoic acid(6-amino-pyridin-2-yl)-amide (49.2 g, 0.26 mol) was dissolved in 500 mLCH₂Cl₂ in a 1000 mL 3-neck flask equipped with mechanical stirring, a125 mL addition funnel and a thermal couple. While stirring, MeSO₃H (50mL, 0.78 mol) was added to the flask dropwise. The exotherm uponaddition was controlled to maintain a temperature <20° C. by anice/water bath. The mixture was allowed to stir for 15 minutes. AlCl₃(274 g, 2.08 mol) was suspended in 1500 mL CH₂Cl₂ in a 5 L 4-neck flaskequipped with mechanical stirring, 1000 mL addition funnel, N₂ line anda thermal couple. To this suspension, the amide solution was addeddropwise. The exotherm from the addition was again controlled tomaintain a temperature <20° C. with an ice/water bath. The reaction wasallowed to warm to room temperature and stir overnight. The reaction hadconsumed all the beta gamma unsaturated isomer and was deemed complete.The reaction mixture was slowly added to ice as an inverse quench. Thequenched mixture was brought to pH 8-10 with 2 N KOH. The saltsprecipitated out of solution and saturated the aqueous phase. Thesuspension was transferred to a separatory funnel and extracted twicewith 100:8:1 CH₂Cl₂:EtOH:NH₄OH. The organic layers were combined, driedover Na₂SO₄, filtered and concentrated to a crude solid. The solid wastriturated with EtOAc and filtered. The resulting solids were puresecond intermediate compound (22.4 g, 0.117 mol, 46%). MS: APCl: M+1:192.2 (Exact Mass: 191.11).

A third intermediate compound,7-Fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one, wasproduced as follows: HF-pyridine (100 mL) was cooled to −42° C. in a1000 mL HDPE bottle using an CH₃CN dry ice bath. While stirringvigorously, 7-amino-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one(24.6 g, 0.129 mol) was added portionwise to control the exotherm. Afterthe addition, NaNO₂ (8.9 g, 0.1291 mol) was added portionwise.Significant exotherms were observed for both additions. The reactionmixture was then allowed to warm to 0° C. and stir for 2 h. The reactionmixture was quenched into a 4 L HDPE bottle full of ice. The aqueousslurry was then neutralized using 2 N KOH. The resulting aqueoussolution was extracted 3 times with CH₂Cl₂. The organic layers weredried over Na₂SO₄, filtered and concentrated to dryness. Excess pyridinewas azeotroped with heptane. The product was dried under vacuum (2 mmHg) for 3 h. The third intermediate compound was isolated as a whitepowder (23.06 g, 0.119 mol, 92%). MS: APCl: M+1: 195.1 (Exact Mass:194.09).

7-Fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one (247 mg,1.272 mmol), 4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (365 mg,1.285 mmol) and sodium t-butoxide (367 mg, 3.82 mmol) were combined in adried flask 3 necked flask under N₂. NMP was added and the solution washeated in an oil bath to 70° C. for 4 hours. The reaction was cooled toroom temperature and poured into ice water. The solid that was collectedwas slurried in CH₂Cl₂ and ethyl acetate and purified by liquidchromatography (MPLC, gradient of 100% CH₂Cl₂ to 100% ethyl acetate) togive the title compound as a foam (280 mg, 0.610 mmol, 48%). MS: APCl:M+1: 459.2 (Exact Mass: 458.27).

EXAMPLE D17 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,7-(4-Hydroxy-butoxy)-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: The7-fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one (5.09 g,26.2 mmol) and butane-1,4-diol (11.81 g, 131.0 mmol) were combined in adried 2-necked flask under N₂. NMP (50 mL) was added and the solutionwas heated in an oil bath to 70° C. overnight. The reaction was cooledto room temperature and poured into ice water. The solid that formed wascollected and triturated in acetonitrile to give the title compound as atan powder (1.72 g). The mother liquor was extracted with CH₂Cl₂, driedover Na₂SO₄, filtered and purified by MPLC (gradient of 100% CH₂Cl₂ to100% ethyl acetate). The compound was isolated as a mixture with diolbyproducts. The title compound was formed as clear crystals (1.09 g)after recrystallization in acetonitrile and another 340 mg was obtainedfrom a second recrystallization. The products were combined to give atotal of 3.15 g of the first intermediate compound (11.9 mmol, 45.5%).MS: APCl: M+1: 265.1 (Exact Mass: 264.15).

A second intermediate compound,4-(5,5-Dimethyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde,was produced as follows:7-(4-Hydroxy-butoxy)-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one(1.72 g, 6.51 mmol) was dissolved in ethyl acetate (50 mL, 0.14 Msolution) and IBX (13 g, 46.4 mmol) was added. The suspension wasimmersed in an oil bath set at 80° C. and stirred vigorously with acondenser. After 1.5 h, the reaction mixture was cooled to roomtemperature and filtered. The filtrate was concentrated to give thesecond intermediate compound as a tan solid (1.62 g, 6.18 mmol, 95%).MS: APCl: M+1: 263.1 (Exact Mass: 262.13).

The naphthyridinones of Examples D17-D25 were synthesized in acombinatorial library format by reductive amination of the appropriatepiperazine starting materials with4-(5,5-dimethyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowing the procedure outlined in Example H7. The final products weremade into hydrochloride salts by treatment with a solution of saturatedHCl in MeOH.

The title compound was isolated (182 mg, 0.381 mmol, 63.5%). MS: APCl:M+1: 477.1 (Exact Mass: 476.17).

EXAMPLE D18 Synthesis of4.4-Dimethyl-7-{4-[4-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was isolated as a hygroscopic foam (149 mg, 0.322mmol, 53.6%). MS: APCl: M+1: 463.2 (Exact Mass: 462.30).

EXAMPLE D19 Synthesis of7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was isolated as a foam (158 mg, 0.352 mmol, 58.7%).MS: APCl: M+1: 449.2 (Exact Mass: 448.28).

EXAMPLE D20 Synthesis of7-{4-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was isolated as a hygroscopic foam (159 mg, 0.349mmol, 58.1%). MS: APCl: M+1: 457.2 (Exact Mass: 456.23).

EXAMPLE D21 Synthesis of7-{4-[4-(3-Chloro-2-methyl-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was isolated as a hygroscopic foam (144 mg, 0.315mmol, 52.5%). MS: APCl: M+1: 457.2 (Exact Mass: 456.23).

EXAMPLE D22 Synthesis of7-{4-[4-(6-Cyclopropyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was isolated as a foam (143 mg, 0.318 mmol, 53.0%).MS: APCl: M+1: 450.2 (Exact Mass: 449.28).

EXAMPLE D23 Synthesis of7-{4-[4-(2-Ethyl-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was isolated as a solid (144 mg, 0.330 mmol, 55%).MS: APCl: M+1: 437.2 (Exact Mass: 436.28).

EXAMPLE D24 Synthesis of7-{4-[4-(2-Isobutoxy-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was isolated as the hydrochloride salt (237 mg, 0.458mmol, 60.1%). MS: APCl: M+1: 481.2 (Exact Mass: 480.31).

EXAMPLE D25 Synthesis of7-{4-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was isolated as the hydrochloride salt (213 mg, 0.423mmol, 55.5%). MS: APCl: M+1: 467.3 (Exact Mass: 466.29).

EXAMPLE E1 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-6-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,7-Benzyloxy-3-methyl-1H-[1,8]naphthyridin-2-one, was produced, adfollows: To a solution of benzyl alcohol (4.3 mL, 41.4 mmol, 2.3 equiv)in DMF (15 mL) was added NaH (1.5 g, 54.0 mmol, 3.0 equiv) in portions.H₂ gas was liberated and the resultant slurry was stirred for 30 minutesat RT. A solution of 7-chloro-3-methyl-1H-[1,8]naphthyridin-2-one (3.5g, 18.0 mmol, 1.0 equiv) in DMF (40 mL) was added to the reactionmixture slowly via a syringe. The reaction mixture was stirred overnightat 100° C., cooled and water was added until all the solids hadprecipitated. The precipitate was collected by filtration and dried togive the first intermediate compound as a pale yellow solid (3.75 g,78%). mp: 220-221° C.; ¹HNMR: (400 MHz, CDCl₃) δ 9.55 (br s, 1H), 7.70(d, 1H), 7.45-7.35 (m, 6H), 6.65 (d, 1H), 5.40 (s, 2H), 2.15 (s, 3H).MS: ES+ 267.02 (M+H)⁺, exact mass: 266.11.

A second intermediate compound,7-Benzyloxy-2-(4-benzyloxy-butoxy)-3-methyl-[1,8]naphthyridine, wasproduced as follows: To a stirred mixture of7-benzyloxy-3-methyl-1H-[1,8]naphthyridin-2-one (2.5 g, 9.4 mmol, 1.0equiv), triphenylphosphine (7.4 g, 28.2 mmol, 3.0 equiv) and 4-benzyloxybutanol (4.9 mL, 28.2 mmol, 3.0 equiv) in THF (250 mL) was added DEAD(4.5 mL, 28.2 mmol, 3.0 equiv) dropwise under nitrogen atmosphere. Thereaction mixture was stirred for 2 hours and quenched with MeOH (10 mL).The solvents were evaporated and the residue was purified by columnchromatography (25% EtOAc/hexanes) to afford the second intermediatecompound as a pale yellow viscous oil (1.27 g, 32%). ¹HNMR: (400 MHz,CDCl₃) δ 7.85 (d, 1H), 7.70 (s, 1H), 7.50-7.25 (m, 10H), 6.85 (d, 1H),5.60 (s, 2H), 4.62 (t, 2H), 4.55 (s, 2H), 3.58 (t, 2H), 2.30 (s, 3H).MS: ES+ 429.07 (M+H)⁺, exact mass: 428.21.

A third intermediate compound,7-(4-Hydroxy-butoxy)-6-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: To a solution of7-benzyloxy-2-(4-benzyloxy-butoxy)-3-methyl-[1,8]naphthyridine (1.25 g,2.92 mmol) in THF (20 mL) and MeOH (100 mL) was added 10% Pd-C (1.0 g)and the mixture was hydrogenated at 40 psi for 48 hours. The reactionmixture was filtered through a celite bed rinsing with MeOH and CH₂Cl₂.The filtrate was concentrated and the residue was purified by columnchromatography (10% MeOH/EtOAc) to afford the third intermediatecompound as a white shiny solid (0.55 g, 76%). mp: 118-119° C.; ¹HNMR:(400 MHz, CDCl₃) δ 7.65 (br s, 1H), 7.20 (s, 1H), 4.30 (t, 2H), 3.75 (t,2H), 2.85 (t, 2H), 2.60 (t, 2H), 2.10 (s, 3H), 1.90-1.85 (m, 2H),1.78-1.62 (m, 2H). MS: ES+ 251.02 (M+H)⁺, exact mass: 250.13.

To a clear solution of the Dess-Martin reagent (0.90 g, 2.12 mmol, 1.3equiv) in CH₂Cl₂ (40 mL) was added7-(4-hydroxy-butoxy)-6-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.40 g, 1.6 mmol, 1.0 equiv) and the mixture was stirred at roomtemperature for 3 hours. TLC indicated the presence of a trace amount ofstarting material and hence more Dess-Martin reagent (0.1 g) was addedand the mixture was stirred for an additional 1 hour. The reactionmixture was diluted with CH₂Cl₂ and poured into a saturated solution ofNaHCO₃ containing Na₂S₂O₃ (2.0 g). The layers were separated and theaqueous layer was extracted with CH₂Cl₂ (2×20 mL). The combined organiclayer was dried over Na₂SO₄ and concentrated. The crude aldehyde wasdissolved in DCE and 1-(2,3-dichlorophenyl)piperazine monohydrochloride,Et₃N and NaBH(OAc)₃ were added. The reaction mixture was stirred for 1hour, diluted with CH₂Cl₂ and washed with saturated NaHCO₃ and brine.The organic layer was dried over Na₂SO4 and concentrated. Purificationof the residue by column chromatography (10% MeOH/EtOAc) gave the titlecompound as a white solid (0.51 g, 54%). mp: 138-139° C.; ¹HNMR: (400MHz, CDCl₃) δ 7.50 (br s, 1H), 7.25-7.15 (m, 3H), 6.95 (m, 1H), 4.25 (t,2H), 3.10 (br s, 4H), 2.82 (t, 2H), 2.65 (br s, 4H), 2.60 (t, 2H), 2.50(t, 2H), 2.10 (s, 3H), 1.80-1.60 (m, 4H). MS: ES+ 463.11 (M+H)⁺, 465.12,exact mass: 462.16.

EXAMPLE E2 Synthesis of6-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

To a clear solution of Dess-Martin reagent (1.40 g, 3.3 mmol, 1.3 equiv)in CH₂Cl₂ (200 mL) was added7-(4-hydroxy-butoxy)-6-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.55 g, 2.2 mmol, 1.0 equiv) and the mixture was stirred at roomtemperature for 4 hours. TLC confirmed the completion of the reaction.The reaction mixture was diluted with CH₂Cl₂ and poured into a saturatedsolution of NaHCO₃ containing Na₂S₂O₃ (3.0g). The mixture was stirredand the organic layer was separated. The aqueous layer was extractedwith CH₂Cl₂ (2×30 mL) and the combined organic layer was dried overNa₂SO₄ and concentrated. The crude aldehyde was dissolved in DCE and1-naphthalen-1-yl-piperazine monohydrochloride (0.76 g, 3.08 mmol, 1.4equiv), Et₃N (0.5 mL, 1.7 equiv) and NaBH(OAc)₃ (0.65 g, 3.08 mmol, 1.4equiv) were added. The reaction mixture was stirred for 1 hour, dilutedwith CH₂Cl₂ and washed with saturated NaHCO₃ and brine. The organiclayer was dried over Na₂SO₄ and concentrated. Purification of theresidue by column chromatography (5% MeOH/EtOAc) gave the title compoundas a white solid (0.40 g, 41%). mp: 76-78° C.; ¹HNMR: (400 MHz, CDCl₃) δ8.22 (d, 1H), 7.85 (d, 1H), 7.58-7.38 (m, 5H), 7.25 (s, 1H), 7.05 (d,1H), 4.25 (t, 2H), 3.30-3.10 (br s, 4H), 2.82-2.65 (m, 4H), 2.65-2.45(m, 4H), 2.15 (s, 3H), 1.88-1.35 (m, 6H). MS: ES+ 445.41 (M+H)⁺, exactmass: 444.25.

EXAMPLE E3 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-6-fluoro-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,6-(4-Benzyloxy-butoxy)-2-chloro-5-fluoro-nicotinonitrile, was producedas follows: To a solution of 4-benzyloxy-1-butanol (19.44 g, 108 mmol)in THF (200 mL) cooled to −40° C. was added 1 M KO^(t)Bu in THF (108 mL,108 mmol). The mixture was stirred for 5 min at −10° C. and then addedto a solution of 2,6-dichloro-5-fluoro-nicotinonitrile (20.0 g, 105mmol) in THF (300 mL) cooled to −70° C. over 25 min. The mixture turnedbrownish yellow with some cloudiness. The reaction was allowed to warmto room temperature over 2 h. The THF was evaporated and the residue wasdiluted with Et₂O. The mixture was washed with water, brine, 1 N citricacid, water and brine, dried over Na₂SO₄ and concentrated to an oil. Theoil was dissolved in Et2O/hexanes and cooled in the refrigeratorovernight. A crystalline solid formed which was collected by filtration,washed with hexanes and dried to give the first intermediate compound asa white solid (17.0 g). The filtrate was concentrated and purified bysilica gel chromatography (Biotage 40L, 0-6% EtOAc/Hexanes) to giveadditional first intermediate compound as a white solid (total of 26.9g, 80.4 mmol, 77%). MS: APCl: M+1: 335.1 (Exact Mass: 334.09).

A second intermediate compound,2-Azido-6-(4-benzyloxy-butoxy)-5-fluoro-nicotinonitrile, was produced asfollows: To a solution of6-(4-benzyloxy-butoxy)-2-chloro-5-fluoro-nicotinonitrile (20.0 g, 60.0mmol) in DMF (40 mL) was added sodium azide (4.27 g, 65.7 mmol) and themixture was heated at 70° C. overnight. The mixture was poured into Et₂Oand washed with water and brine. The Et₂O solution was passed through asilica gel Biotage 12M column, dried over MgSO₄ and charcoal, andconcentrated to give an oil (19.67 g). Recrystallization from Et₂O/MeOHgave the second intermediate compound as a solid (17.24 g, 50.5 mmol,84%). MS: APCl: M+1: (Exact Mass: 341.13).

A third intermediate compound,2-Amino-6-(4-benzyloxy-butoxy)-5-fluoro-nicotinonitrile, was produced asfollows: To a solution of2-azido-6-(4-benzyloxy-butoxy)-5-fluoro-nicotinonitrile (17.2 g, 50.4mmol) in MeOH (450 mL) was added hexamethyldisilthiane (19.0 g, 106.5mmol). The reaction gives off a gas and a precipitate forms after 15min. The reaction was stirred overnight at room temperature and thenfiltered to remove the precipitated sulfur. The mixture was concentratedand then redissolved in Et₂O. The mixture was filtered again to removeadditional precipitated sulfur. The filtrate was concentrated andrecrystallized from MeOH/hexanes. The solid was collected by filtration,washed with hexane/MeOH and dried to give the third intermediatecompound (13.74 g, 43.57 mmol, 86%). MS: APCl: M+1: 316.4 (Exact Mass:315.14).

A fourth intermediate compound,2-Amino-6-(4-benzyloxy-butoxy)-5-fluoro-pyridine-3-carbaldehyde, wasproduced as follows: To a solution of2-amino-6-(4-benzyloxy-butoxy)-5-fluoro-nicotinonitrile (7.25 9, 23.0mmol) in THF (40 mL) cooled to 0° C. is added DIBALH (1M in THF, 69 mL,69 mmol). The reaction was complete after 5 min. Chilled 2N HCl wasadded very slowly (strong exotherm) to quench the reaction. The mixtureforms a red gelatinous material. Et₂O was added and the layers wereseparated. The organic layer was washed with brine and saturated NaHCO₃and then filtered through Celite. There may still have been somealuminum complexed product so the organic solution was washed again with2N HCl, brine, saturated NaHCO₃ and brine, dried over MgSO₄ andconcentrated to give the crude fourth intermediate compound as an orangeoil (5.23 g, 16.4 mmol, 71%). MS: APCl: M+1: 319.2 (Exact Mass: 318.14).

A fifth intermediate compound,3-[2-Amino-6-(4-benzyloxy-butoxy)-5-fluoro-pyridin-3-yl]-acrylic acidethyl ester, was produced as follows: To a solution of2-amino-6-(4-benzyloxy-butoxy)-5-fluoro-pyridine-3-carbaldehyde (5.23 g,16.4 mmol, crude from previous reaction) in THF (50 mL) was added(carbethoxymethylene)triphenylphosphorane (5.72 g. 16.43 mmol) and thesolution was heated at 67° C. overnight. The reaction was concentratedand the residue was purified by liquid chromatography (Biotage 65M,0-10% EtOAc/CH₂Cl₂) to give the fifth compound as a yellow solid (73%).MS: APCl: M+1: 389.4 (Exact Mass: 388.18).

A sixth intermediate compound,7-(4-Benzyloxy-butoxy)-6-fluoro-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows:3-[2-Amino-6-(4-benzyloxy-butoxy)-5-fluoro-pyridin-3-yl]-acrylic acidethyl ester (7.18 g, 18.5 mmol) was hydrogenated under an atmosphere ofH₂ (4300 psi) using Ra—Ni (2 g) in MeOH (100 mL). The reaction wasfiltered and concentrated. MS indicated the double bond had been reducedand some of the material cyclized. The material was suspended in^(i)PrOH and p-toluenesulfonic acid hydrate (0.41 g) was added. Themixture was heated at 80° C. for 30 min. Saturated NaHCO₃ was added andthe mixture was concentrated. The residue was partitioned between Et₂Oand water. The organic layer was washed with saturated NaHCO₃ and brine,dried over MgSO₄ and concentrated to give a yellow oil which solidified.Recrystallization from Et₂O/hexane afforded the sixth intermediatecompound as a pale yellow solid. MS: APCl: M+1: 345.1 (Exact Mass:344.15).

A seventh intermediate compound,6-Fluoro-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows:7-(4-Benzyloxy-butoxy)-6-fluoro-3,4-dihydro-1H-[1,8]naphthyridin-2-one(4.79 g, 13.9 mmol) was hydrogenated under an atmosphere of H₂ using 20%Pd/C (1.0 g) in EtOH (100 mL). The reaction was filtered andconcentrated to give a slurry. Et₂O was added and the solids werefiltered. The filtrate was concentrated and the process was repeated togive the seventh intermediate compound as a solid (3.2 g, 13.0 mmol,91%). MS: APCl: M+1: 255.1 (Exact Mass: 254.11).

An eighth intermediate compound,4-(3-Fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde,was produced as follows: To a solution of oxalyl chloride (1.78 g, 14.0mmol) in CH₂Cl₂ (25 mL) cooled to −70 ° C. was added a solution of DMSO(2.15 g, 27.6 mmol) in CH₂Cl₂ (1.5 mL) over 4 min. The mixture wasstirred for 5 min and a solution of6-fluoro-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one(3.1 g, 12.0 mmol) in DMSO (4.5 mL) and CH₂Cl₂ (44 mL) cooled to −50° C.was added over 5 min. The mixture was stirred for 10 min at −70° C. andit solidified. The reaction was warmed to −30° C. and triethylamine (8.9mL, 63.8 mmol) was added resulting in a stirable suspension. Thereaction was warmed to room temperature over 30 min. The mixture wasadded to water and the layers were separated. The organic layer waswashed with water and dilute brine, dried over MgSO₄ and concentrated togive an oil. The residue was partitioned between Et₂O and aqueous citricacid (pH 4.5). The organic layer was washed with dilute aqueous NaHCO₃and brine, dried over MgSO₄ and concentrated to give the eighthintermediate compound as a yellow oil (1.89 g) which was used directlyin the next reaction. MS: APCl: M+1: 253.2 (Exact Mass: 252.09).

To a suspension of 1-(2,3-dichloro-phenyl)-piperazine hydrochloride(0.80 g, 3.0 mmol) in 1,2-dichloroethane (10 mL) was added triethylamine(0.61 mL, 6.0 mmol). The mixture was stirred for 30 min at roomtemperature and4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(0.76 g, 3.0 mmol) was added as a suspension in 1,2-dichloroethane (5mL). The mixture was stirred for 30 min and NaBH(OAc)₃ (0.89 g, 4.2mmol) was added as a solid. The reaction was stirred at room temperaturefor 4 h. The mixture was poured into EtOAc/dichloroethane and washedwith saturated NaHCO₃ and brine. The organic layer was washed withaqueous citric acid (pH 4.5) and brine, dried over Na₂SO₄ andconcentrated to a slurry. Et₂O was added and the solid was collected byfiltration. Purification by liquid chromatography (Biotage 40S, gradientof CH₂Cl₂ to 10% MeOH/CHCl₃) gave the title compound as a white solid(738 mg, 1.58 mmol, 53%). MS: APCl: M+1: 467.3 (Exact Mass: 466.13).

EXAMPLE E4 Synthesis of 6-Fluoro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was prepared by reductive amination of4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydewith 1-naphthalen-1-yl-piperazine hydrochloride according to the aboveprocedure. MS: APCl: M+1: 449.1 (Exact Mass: 448.23).

EXAMPLE E5 Synthesis of6-Fluoro-7-[4-(4-indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was prepared by reductive amination of4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydewith 1-indan-4-yl-piperazine according to the above procedure. MS: APCl:M+1: 439.2 (Exact Mass: 438.24).

EXAMPLE E6 Synthesis of6-Chloro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,6-Chloro-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: To a solution of7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (2.0 g, 8.46mmol) in DMF (17 mL) was added NCS (1.24 g, 9.31 mmol). The solution wasstirred at room temperature for 1 hour. There was no reaction so themixture was heated at 80° C. for 5 hours. Water was added and themixture was extracted with EtOAc. The organic layer was washed withwater and brine, dried over Na₂SO₄ and concentrated. Purification byliquid chromatography (0-5% MeOH/CH₂Cl₂) gave the first intermediatecompound as an off-white solid (0.71 g, 2.62 mmol, low yield was due tochromatography mishap). MS: APCl: M+1: 271.0 (Exact Mass: 270.08).

A second intermediate compound,4-(3-Chloro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde,was produced as follows: A suspension of the Dess-Martin reagent (1.67g, 3.93 mmol) in CH₂Cl₂ (6 mL) was stirred for 30 min and a solution of6-chloro-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one(0.71 g, 2.62 mmol) in CH₂Cl₂ (5 mL)/THF (15 mL) was added via cannula.The reaction mixture became homogenous and turned yellow. The reactionwas stirred at room temperature for 6 h. A 1:1 mixture of saturatedNaHCO₃ and saturated Na₂S₂O₃ was added and the mixture was stirred for15 min. The mixture was extracted with EtOAc (2×). The organic layer waswashed with saturated NaHCO₃ and brine, dried over MgSO₄ andconcentrated to give a yellow solid (0.74 g, approx. 80% pure, usedcrude in the next reaction). MS: APCl: M+1: 269.0 (Exact Mass: 268.06).

To a solution of4-(3-chloro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(400 mg, approx. 1.49 mmol, crude from previous reaction) in DCE (7 mL)was added 1-naphthalen-1-yl-piperazine hydrochloride (370 mg, 1.49 mmol)followed by Et₃N (0.42 mL, 2.98 mmol). The solution was stirred for 15min and NaBH(OAc)₃ (410 mg, 1.94 mmol) was added as a powder. Thereaction was stirred at room temperature for 2 h and quenched withsaturated NaHCO₃ and H₂O. The mixture was extracted with EtOAc. Theorganic layer was washed with saturated NaHCO₃, H₂O and brine, driedover Na₂SO₄ and concentrated. Purification by liquid chromatography(0-3% MeOH/CH₂Cl₂) afforded the title compound as an off-white foam (324mg, 0.697 mmol, 47%). Et₂O was added and the foam turned into a whitesolid after 5 minutes of stirring. The solid was collected byfiltration, washed with Et₂O and dried to give a white solid. MS: APCl:M+1: 465.2 (Exact Mass: 464.20).

EXAMPLE E7 Synthesis of6-Bromo-7-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,6-Bromo-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one, wasproduced as follows: To a solution of7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (2.0 g, 8.46mmol) in DMF (18 mL) was added NBS (1.70 g, 9.30 mmol). The solution wasstirred at room temperature overnight. Within 2 hours, the reaction hadturned purple. Water was added and the mixture was extracted with EtOAc.The organic layer was washed with water and brine, dried over Na₂SO₄ andconcentrated to give a brown oil. Purification by liquid chromatography(0-5% MeOH/CH₂Cl₂) gave the first intermediate compound as an off-whitesolid (2.13, 6.76 mmol, 80%). MS: APCl: M+1: 315.0, 317.0 (Exact Mass:314.03).

A second intermediate compound,4-(3-Bromo-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde,was produced as follows: A suspension of the Dess-Martin reagent (3.28g, 7.74 mmol) in CH₂Cl₂ (15 mL) was stirred for 30 min and a solution of6-bromo-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one(1.524 g, 4.84 mmol) in CH₂Cl₂ (5 mL)/THF (20 mL) was added via cannula.The reaction mixture became homogenous and turned yellow. The reactionwas stirred at room temperature for 6 h and then stored in therefrigerator overnight. A 1:1 mixture of saturated NaHCO₃ and saturatedNa₂S₂O₃ was added and the mixture was stirred for 15 min. The mixturewas extracted with EtOAc (2×). The organic layer was washed withsaturated NaHCO₃ and brine, dried over Na₂SO₄ and concentrated to give ayellow solid/oil (1.51 g, used crude in the next reaction). MS: APCl:M+1: 313.0, 315.0 (Exact Mass: 312.01).

To a solution of4-(3-bromo-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(0.43 g, approx. 1.37 mmol, crude from previous reaction) in DCE (6 mL)was added 1-(2,3-dichloro-phenyl)-piperazine hydrochloride (367 mg, 1.37mmol) followed by Et₃N (0.38 mL, 2.75 mmol). The solution was stirredfor 15 min and NaBH(OAc)₃ (407 mg, 1.92 mmol) was added as a powder. Thereaction was stirred at room temperature for 2 h and quenched withsaturated NaHCO₃ and H₂O. The mixture was extracted with EtOAc. Theorganic layer was washed with saturated NaHCO₃, H₂O and brine, driedover Na₂SO₄ and concentrated. Purification by liquid chromatography (4%MeOH/CH₂Cl₂) afforded the title compound as a white foam (497 mg, 0.941mmol, 69%). MS: APCl: M+1: 527.0,529.0,531.0 (Exact Mass: 526.05).

EXAMPLE E8 Synthesis of6-Bromo-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

To a solution of4-(3-bromo-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(1.11 g, approx. 3.54 mmol, crude) in DCE (17 mL) was added1-naphthalen-1-yl-piperazine hydrochloride (0.882 g, 3.54 mmol) followedby Et₃N (1.0 mL, 7.1 mmol). The solution was stirred for 15 min andNaBH(OAc)₃ (1.05 g, 4.96 mmol) was added as a powder. The reaction wasstirred at room temperature for 2 h and quenched with saturated NaHCO₃and H₂O. The mixture was extracted with EtOAc. The organic layer waswashed with saturated NaHCO₃, H₂O and brine, dried over Na₂SO₄ andconcentrated. Purification by liquid chromatography (4% MeOH/CH₂Cl₂)afforded the title compound as an off-white foam (1.37 g, 2.69 mmol,76%). The HCl salt was formed by dissolving the title compound (138 mg,0.27 mmol) in Et₂O/CH₂Cl₂ followed by the addition of 1N HCl in Et₂O(0.3 mL). The resulting white precipitate was collected by filtration,washed with Et₂O and dried to give a white solid (125 mg). MS: APCl:M+1: 509.1,511.1 (Exact Mass: 508.15).

EXAMPLE E9 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-5-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,N-(7-Hydroxy-5-methyl-[1,8]naphthyridin-2-yl)-acetamide, was produced asfollows: A suspension of 7-amino-4-methyl-[1,8]naphthyridin-2-ol (25.6g, 146 mmol) in acetic anhydride (375 mL) was heated at reflux for 4.5hours. The mixture was filtered hot and washed with acetic anhydride andEt₂O. The resulting solid was dried to give the first intermediateproduct (28.8 g, 132.6 mmol, 91%, >95% purity). Calcd for C₁₁H₁₁N₃O₂: C60.82, H 5.10, N 19.34; Found C 60.88, H 5.03, N 19.39.

A second intermediate compound,N-(7-Chloro-5-methyl-[1,8]naphthyridin-2-yl)-acetamide, was produced asfollows: N-(7-Hydroxy-5-methyl-[1,8]naphthyridin-2-yl)-acetamide (28.5g, 131.2 mmol) was suspended in POCl₃ (280 mL) and heated to reflux for90 min giylng a dark solution. The reaction was quenched by slowlyadding it to a 3 L flask containing ice with mechanical stirring (totalvolume of 1 L). The mixture was cooled and neutralized to pH 6.5 using15% to 50% aqueous NaOH to give a precipitate. The mixture was filteredovernight, washed with H₂O and dried to give a light brown solid (36 g,contains product and deacetylated compound). The solid was suspended inrefluxing toluene and the mixture was filtered while hot. The insolublesolids were mostly more polar side products. The filtrate was cooled togive a precipitate which was collected by filtration and washed withtoluene to give material that was enriched in the desired product. Thissolid was suspended in CH₂Cl₂ and the insoluble material was collectedby filtration to give pure second intermediate compound. Severaladditional crops were collected (total of 18.5 g, 78.5 mmol, 60%). MS:APCl: M+1: 236.1, 238.1 (Exact Mass: 235.05).

A third intermediate compound,7-Chloro-5-methyl-[1,8]naphthyridin-2-ylamine, was produced as follows:N-(7-Chloro-5-methyl-[1,8]naphthyridin-2-yl)-acetamide (11.5 g, 48.8mmol) was suspended in 10% H₂SO₄ (180 mL). The mixture was heated at110° C. for 2 h and filtered hot to remove the minor insoluble solids.H₂O (180 mL) was added to the filtrate and a precipitate formed. Themixture was heated again to give a solution. The heating was removed andconcentrated NH₄OH was added with rapid stirring until the mixture wasat pH 10. The mixture was cooled and the precipitate was collected byfiltration, washed with H₂O and dried to give the third intermediatecompound as a pale yellow solid (9.24 g, 47.7 mmol, 98%). mp 264-266° C.MS: APCl: M+1: 194.0,196.0 (Exact Mass: 193.04).

A fourth intermediate compound,7-Chloro-5-methyl-1H-[1,8]naphthyridin-2-one, was produced as follows:To a mixture of 7-chloro-5-methyl-[1,8]naphthyridin-2-ylamine (13.7 g,70.7 mmol) in concentrated H₂SO₄ (55 mL) cooled to 0° C. was added asolution of NaNO₂ (6.3 g, 92.0 mmol) in H₂O (25 mL) dropwise. AdditionalH₂O was added and the mixture was stirred at 20° C. for 1 h. The mixturewas poured into ice. The resulting precipitate was filtered, washed withH₂O, EtOH and Et₂O and dried to give the fourth intermediate compound asa powder (13.45 g, 69.1 mmol, 98%).

A fifth intermediate compound,7-(4-Benzyloxy-butoxy)-5-methyl-1H-[1,8]naphthyridin-2-one, was producedas follows: To a suspension of 60% NaH (5.7 g, 144 mmol, washed with THFto remove the oil) in DMF (80 mL) was added 4-benzyloxy-1-butanol (25.0g, 137 mmol) slowly. The mixture was warmed to 70° C. and then cooled toRT. This mixture was added to a suspension of7-chloro-5-methyl-1H-[1,8]naphthyridin-2-one (12.7 g, 65.3 mmol) in DMF(40 mL) to give a brown solution. The mixture was heated at 90° C. for30 min and at 120° C. for 2 h. The reaction was allowed to cool to roomtemperature and stir overnight. The reaction was poured into aseparatory funnel and Et₂O was added followed by a minimal amount ofH₂O. The ether phase contained excess 4-benzyloxy-1-butanol. The pH ofthe DMF/aqueous layer was adjusted to 11.5 by adding 1 N citric acid anda precipitate formed. The precipitate was filtered and washed with Et₂O.The solid was resuspended in H₂O (100 mL) and EtOH (200 mL) was added todissolve the solid. The mixture was filtered through celite to removethe insoluble solids. The filtrate was diluted with H₂O (700 mL) and apale yellow solid precipitated. The solid was collected by filtration,washed with H₂O and dried to give the fifth intermediate compound as asolid (7.38 g, 21.8 mmol, 33%). MS: APCl: M+1: 339.2 (Exact Mass:338.16).

A sixth intermediate compound,7-(4-Hydroxy-butoxy)-5-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows:7-(4-Benzyloxy-butoxy)-5-methyl-1H-[1,8]naphthyridin-2-one (7.31 g, 21.6mmol) was hydrogenated using 20% Pd/C (1.0 g) in EtOH (100 mL). Theproduct precipitated out of solution before the double bond was reduced.DMF (75 mL) was added and the mixture was heated to dissolve the solids.More 20% Pd/C (1.0 g) was added and the hydrogenation was continued,however the double bond was resistant to further hydrogenation underthese conditions. The reaction mixture was filtered and the solvent wasconcentrated to give a slurry. Et₂O was added and the solid wascollected by filtration and dried to give7-(4-hydroxy-butoxy)-5-methyl-1H-[1,8]naphthyridin-2-one (4.37 g, 17.6mmol, 81 %).

7-(4-Hydroxy-butoxy)-5-methyl-1H-[1,8]naphthyridin-2-one (3.0 g, 12.08mmol) was hydrogenated using 20% Pd/C in acetic acid ( mL) for x h. Thereaction mixture was filtered and concentrated to give a mixture of thesixth intermediate compound and the corresponding acetylated compound.The mixture was suspended in MeOH (30 mL) and H₂O (10 mL) and the pH wasadjusted to 14 by addition of 50% aqueous NaOH. The mixture was warmedto 45° C. Glacial acetic acid was added to bring the pH to 7.5 and theMeOH was removed under reduced pressure. The resulting solid wasfiltered, washed with H₂O and dried to give the sixth intermediatecompound as a solid (2.78 g, 11.1 mmol, 92%). MS: APCl: M+1: 251.1(Exact Mass: 250.13).

A seventh intermediate compound,4-(4-Methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde,was produced as follows: To a solution of oxalyl chloride (1.57 g, 12.4mmol) in CH₂Cl₂ (20 mL) cooled to −70° C. was added a solution of DMSO(1.90 g, 24.38 mmol) in CH₂Cl₂ (4 mL) over 4 min. The mixture wasstirred for 5 min and a solution of7-(4-hydroxy-butoxy)-5-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one(2.70 g, 11.0 mmol) in DMSO (8 mL) and CH₂Cl₂ (40 mL) was added over 5min. The reaction was stirred at −70 ° C. for 10 min and a solidprecipitated. The mixture was warmed to −50° C. for 5 min and recooledto −70° C. Et₃N (7.9 mL, 56.4 mmol) was added and the mixture was warmedto room temperature over 30 min. The reaction mixture was added to H₂Oand the layers were separated. The organic layer was washed with H₂O, 1Ncitric acid (2×) and saturated NaHCO₃, dried over Na₂SO₄ andconcentrated to a slurry. Et₂O was added and the solid was collected byfiltration to give the seventh intermediate compound (2.38 9, 9.59 mmol,89%). MS: APCl: M+1: 249.2 (Exact Mass: 248.12).

To a suspension of 1-(2,3-dichloro-phenyl)-piperazine hydrochloride(0.93 g, 3,48 mmol) in dichloroethane (10 mL) was added Et₃N (0.96 mL,6.92 mmol). The mixture was stirred for 15 min and a suspension of4-(4-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(0.86 g, 3,46 mmol) in dichloroethane (5 mL) was added. After 20 min atRT, NaBH(OAc)₃ (1.03 g, 4.85 mmol) was added and the reaction wasstirred at room temperature for 4 h. The reaction mixture was pouredinto CH₂Cl₂ and washed with H₂O, 1N citric acid, saturated NaHCO₃ andbrine, dried over Na₂SO₄ and concentrated to an oil. Et₂O was added andthe organics were decanted from an insoluble gum. The filtrate yielded acrystalline solid, which was collected by filtration and dried.Purification by liquid chromatography (gradient elution, 100% CHCl₃ to2% MeOH/CHCl₃, Biotage 40m column) provided the title compound as awhite solid (1.12 g, 2.44 mmol, 70%). MS: APCl: M+1: 463.1 (Exact Mass:462.16).

EXAMPLE E10 Synthesis of5-Methyl-7-[4-(4-naphthalen-1-yl-pirerazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was prepared by reductive amination of4-(4-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydewith 1-naphthalen-1-yl-piperazine hydrochloride according to the aboveprocedure. MS: APCl: M+1: 445.2 (Exact Mass: 444.25).

EXAMPLE E11 Synthesis of5-Methyl-7-{4-[4-(5.6.7.8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was prepared by reductive amination of4-(4-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydewith 1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine according to theabove procedure. MS: APCl: M+1: 450.0 (Exact Mass: 448.28).

EXAMPLE E12 Synthesis of7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-5-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was prepared by reductive amination of4-(4-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydewith 1-indan-4-yl-piperazine according to the above procedure. MS: APCl:M+1: 435.6 (Exact Mass: 434.27).

EXAMPLE E13 Synthesis of7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-5-trifluoromethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,6-(4-Benzyloxy-butoxy)-2-chloro-4-trifluoromethyl-nicotinonitrile, wasproduced as follows: A solution of2,6-dichloro-4-(trifluoromethyl)niconitrile (20 g, 83 mmol) in THF (200mL) was cooled to −70° C. Separately, a solution of4-benzyloxy-1-butanol (15.41 g, 85.5 mmol) in THF (150 mL) was cooled to−40° C. and 1M potassium t-butoxide in THF (85.5 mL) was added dropwiseand the temperature was allowed to reach 10° C. over 15 minutes. Thesolution thus prepared was added to the solution of2,6-dichloro-4-(trifluoromethyl)niconitrile at −70° C. over 2 hours,followed by warming to 25° C. for 16 hours. The THF was removed in vacuoand the residue was partitioned between ether and water. The ether phasewas washed with 1N citric acid, brine, dried over magnesium sulfate andfiltered. The filtrate was evaporated to an oil, which was sufficientlypure to be used in the next step.

A second intermediate compound,2-Azido-6-(4-benzyloxy-butoxy)-4-trifluoromethyl-nicotinonitrile, wasproduced as follows: To DMF (60 mL) was added6-(4-benzyloxy-butoxy)-2-chloro-4-trifluoromethyl-nicotinonitrile (32 g,83.1 mmol) and sodium azide (5.9 g, 91 mmol) followed by heating at 70°C. for 16 hours. The mixture was partitioned between water and ether.The ether phase was washed with brine, dried over magnesium sulfate,filtered and evaporated to give the second intermediate compound as anoil (30.7 g) of sufficient purity to be used in the next step.

A third intermediate compound,2-Amino-6-(4-benzyloxy-butoxy)-4-trifluoromethyl-nicotinonitrile, wasproduced as follows: To a solution of2-azido-6-(4-benzyloxy-butoxy)-4-trifluoromethyl-nicotinonitrile (30.7g, 78.5 mmol) in methanol (150 mL) cooled to 0° C. was added1,1,1,3,3,3-hexamethyl-disilathiane (28.02 g, 157 mmol). The reactionwas exothermic and off-gassing occurred over 3 hours. A minor amount ofprecipitate was filtered off and the filtrate was refrigerated giylng asolid precipitate. The solid was filtered, washed with hexane and driedto a weight of 19.7 g. The solid was purified by chromatography onsilica gel eluting with dichloromethane to give the third intermediatecompound as a solid (6.08 g), mp 94-96° C.

A fourth intermediate compound,2-Amino-6-(4-benzyloxy-butoxy)-4-trifluoromethyl-pyridine-3-carbaldehyde,was produced as follows: To solution of2-amino-6-(4-benzyloxy-butoxy)-4-trifluoromethyl-nicotinonitrile (8.76g, 24 mmol) in THF (40 mL) cooled to 0° C. was added 1M DIBAL in THF (96mL). After warming to 25° C. for 1 hour, the mixture was quenched byaddition of a solution of cold 2N HCl (200 mL). After stirring andwarming to 25° C., the mixture was neutralized to pH 7 by addition ofpotassium carbonate and the mixture extracted with diethyl ether. Theether washings were dried over magnesium sulfate, filtered andevaporated to give the fourth intermediate compound as an oil (7.5 g).

A fifth intermediate compound,3-[2-Amino-6-(4-benzyloxy-butoxy)-4-trifluoromethyl-pyridin-3-yl]-acrylicacid ethyl ester, was produced as follows: To a solution of2-amino-6-(4-benzyloxy-butoxy)-4-trifluoromethyl-pyridine-3-carbaldehyde(4.66 g, 10.6 mmol) in methanol (100 mL) was added(triphenylphosphanylidene) acetic acid ethyl ester (7.09 g, 20.4 mmol).The mixture was heated to 67° C. for 16 hours and evaporated to an oil.Purification by chromatography on silica gel eluting with hexane/ethylacetate provided the fifth intermediate compound as an oil (4.66 g).

A sixth intermediate compound,7-(4-Benzyloxy-butoxy)-5-trifluoromethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: To a solution of3-[2-amino-6-(4-benzyloxy-butoxy)-4-trifluoromethyl-pyridin-3-yl]-acrylicacid ethyl ester (7.5 g, 20 mmol) in THF (70 mL) was added Raney Nickel(1.5 g). The reaction was pressurized to 50 psi with hydrogen gas for 16hours. The mixture was filtered, evaporated to an oil, redissolved inisopropanol (20 mL) and p-toluene sulfonic acid (0.24 g) was added. Themixture was heated at reflux for 45 minutes. The mixture was poured intoa mixture of saturated sodium carbonate and diethyl ether and the etherphase was separated. The ether layer was washed with brine, dried overanhydrous magnesium sulfate, filtered and evaporated to give the sixthintermediate compound as an oil (3.29 g).

A seventh intermediate compound,7-(4-Hydroxy-butoxy)-5-trifluoromethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: To a 50:50 mixture of THF/methanol (50 mL) wasadded7-(4-benzyloxy-butoxy)-5-trifluoromethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one(3.29 g, 8.3 mmol) followed by 20% Pd on charcoal (2.0 g). The reactionwas pressurized to 50 psi with hydrogen gas for 48 hours. The mixturewas filtered and evaporated to give the seventh intermediate compound asa solid (3.29 g).

An eighth intermediate compound,4-(7-Oxo-4-trifluoromethyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde,was produced as follows: To a solution of oxallyl chloride (1.1 g, 8.77mmol) and DMSO (1.35 g, 17.2 mmol) in dichloromethane (20 mL) at −70° C.was added a solution of7-(4-hydroxy-butoxy)-5-trifluoromethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one(2.32 g, 7.62 mmol) in DMSO over 10 minutes. To the mixture was addedtriethylamine (4.0 g, 40 mmol) and the reaction was warmed to 25° C.over 45 minutes. The mixture was washed consecutively with 1N citricacid, saturated sodium bicarbonate and brine, followed by drying of theorganic phase over magnesium sulfate and filtration. The filtrate wasevaporated to give the eighth intermediate compound as a solid (2.28 g).

In a manner similar to that of other examples above,1-indan-4-yl-piperazine hydrochloride was coupled by reductive aminationto4-(7-oxo-4-trifluoromethyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowed by typical workup and purification to give the title compound.MS: APCl: M+1: 489.4 (Exact Mass: 488.24).

EXAMPLE E14 Synthesis of7-[4-(4-Napthalen-1-yl-piperazin-1-yl)-butoxy]-5-trifluoromethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

In a manner similar to that of other examples above,1-naphthalen-1-yl-piperazine hydrochloride was coupled by reductiveamination to4-(7-oxo-4-trifluoromethyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowed by typical workup and purification to give the title compound.MS: APCl: M+1: 499.1 (Exact Mass: 489.22).

EXAMPLE E15 Synthesis of7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5-trifluoromethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

In a manner similar to that of other examples above,1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine was coupled byreductive amination to4-(7-oxo4-trifluoromethyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowed by typical workup and purification to give the title compound.MS: APCl: M+1: 503.1 (Exact Mass: 502.26).

EXAMPLE F1 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

A first intermediate compound,N-{3-Hydroxymethyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,2-dimethyl-propionamide,was produced as follows: An ice-cold mixture ofN-{3-formyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,2-dimethyl-propionamide(2.20 g, 5.80 mmol) in methanol (20 mL) was treated with NaBH₄ (0.394 g,10.40 mmol) in portions. Bubbles evolved from the mixture. The mixturewas warmed to room temperature and stirred for 1 hour. The colorlesssolution was quenched with water and concentrated under vacuum. Theresidue was diluted with water and EtOAc. The organic layer wasseparated and the aqueous layer was extracted with EtOAc. The combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered,and concentrated under vacuum to afford the first intermediate compoundas a yellow oil (2.21 g, quantitative). ¹H NMR (400 MHz, CDCl₃): δ 7.69(d, 1H), 7.68 (br s, 1H), 6.62 (d, 1H), 4.62-4.58 (m, 1H), 4.38 (d, 2H),4.26 (t, 2H), 4.04-3.96 (m, 1H), 3.92-3.77 (m, 2H), 3.55-3,42 (m, 2H),1.92-1.67 (m, 6H), 1.63-1.48 (m, 4H), 1.36 (s, 9H). MS ES: m/z=381.10.

A second intermediate compound,N-{3-Azidomethyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,2-dimethyl-propionamide,was produced as follows: An ice-cold mixture ofN-{3-hydroxymethyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,2-dimethyl-propionamide(1.00 g, 2.60 mmol) and diphenylphosphoryl azide (1.44 g, 4.20 mmol) intoluene was treated with DBU (7.27 g, 4.78 mmol). The reaction mixturewas warmed to room temperature and stirred for 1 hour. The brown mixturewas concentrated under vacuum and diluted with EtOAc and water. Theorganic layer was separated and the aqueous layer was extracted withEtOAc. The combined organic extracts were dried over Na2SO₄, filteredand concentrated under vacuum. The residue was purified by columnchromatography (3:1, hexanes/EtOAc) to afford the second intermediatecompound as a light yellow oil (0.800 g, 75 %). ¹H NMR (400 MHz, CDCl₃):δ 7.63 (d, 1H), 7.58 (s, 1H), 6.62 (d, 1H), 4.62-4.59 (m, 1H), 4.30 (s,2H), 4.26 (s, 2H), 3.92-3.77 (m, 2H), 3.54-3,42 (m, 2H), 1.92-1.67 (m,6H), 1.63-1.46 (m, 4H), 1.35 (s, 9H). MS ES: m/z=406.10.

A third intermediate compound,N-[3-Azidomethyl-6-(4-hydroxy-butoxy)-pyridin-2-yl]-2,2-dimethyl-propionamide,was produced as follows: A mixture ofN-{3-azidomethyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,2-dimethyl-propionamide(0.730 g, 1.80 mmol), pyridinium p-toluenesulphonic acid (0.100 g, 0.40mmol) in EtOH (50 mL) was refluxed for 1 hour. The solution wasconcentrated under vacuum, then diluted with water and EtOAc. Theorganic layer was separated and the aqueous layer was extracted withEtOAc. The combined organic extracts were dried over Na₂SO₄, filteredand concentrated under vacuum to afford the third intermediate compoundas a yellow oil (0.570 g, 99 %). ¹H NMR (400 MHz, CDCl₃): δ 7.70-7.62(br s, 1H), 7.63 (d, 1H), 6.63 (d, 1H), 4.31 (s, 2H), 4.29 (t, 2H), 3.73(t, 2H), 1.92-1.82 (m, 2H), 1.78-1.68 (m, 3H), 1.35 (s, 9H). MS ES:m/z=322.20.

A fourth intermediate compound,N-[3-Azidomethyl-6-(4-oxo-butoxy)-pyridin-2-yl]-2,2-dimethyl-propionamide,was produced as follows: A solution of Dess-Martin periodinane (0.982 g,2.20 mmol) in CH₂Cl₂ (20 mL) was treated withN-[3-azidomethyl-6-(4-hydroxy-butoxy)-pyridin-2-yl]-2,2-dimethyl-propionamide(0.470 g, 1.46 mmol) in CH₂Cl₂ (5 mL) at RT. The yellow mixture wasstirred for 1.5 hours, then diluted with Et₂O and poured into saturatedNaHCO₃ containing Na₂S₂O₃ (2.50 g, 15.80 mmol). The mixture was stirredfor 10 minutes and the organic layer was separated. The aqueous layerwas extracted with Et₂O and the combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered and concentrated under vacuum toafford the crude aldehyde, which was used in the next step withoutfurther purification.

A fifth intermediate compound,N-(3-Azidomethyl-6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-pyridin-2-yl)-2,2-dimethyl-propionamide,was produced as follows: To a solution ofN-[3-azidomethyl-6-(4-oxo-butoxy)-pyridin-2-yl]-2,2-dimethyl-propionamidein DCE (50 mL) was added 1-(2,3-dichlorophenyl)piperazine (0.553 g, 2.10mmol), Et₃N (0.295 g, 2.90 mmol) and NaBH(OAc)₃ (0.433 g, 2.00 mmol).The mixture was stirred at room temperature for 1 hour, then quenchedwith water and saturated NaHCO₃. The mixture was extracted with CH₂Cl₂and the combined extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography (10% MeOH/EtOAc) to afford the fifth intermediatecompound as a yellow oil (0.455 g, 58 %). ¹H NMR (400 MHz, CDCl₃): δ7.62 (d, 1H), 7.61-7.55 (br s, 1H), 7.20-7.14 (m, 2H), 7.00-6.92 (m,1H), 6.61 (d, 1H), 4.33 (s, 2H), 4.27 (t, 2H), 3.18-3.00 (m, 4H),2.78-2.58 (m, 4H), 2.47-2.41 (m, 2H), 1.89-1.62 (m, 4H), 1.36 (s, 9H).MS ES: m/z=534.09, 536.04.

A sixth intermediate compound,[6-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-2-(2,2-dimethyl-propionylamino)-pyridin-3-ylmethyl]-carbamicacid tert-butyl ester, was produced as follows: A mixture ofN-(3-azidomethyl-6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-pyridin-2-yl)-2,2-dimethyl-propionamide(0.808 g, 1.51 mmol) and di-tert-butyl dicarbonate (0.326 g, 1.54 mmol)in EtOH (40 mL) was treated with Raney-Nickel (2 mL suspension inwater). The mixture was shaken under 45 psi of H₂ for 3 hours. Thesuspension was filtered through Celite and the Celite pad was washedwith EtOH. The filtrate was concentrated in vacuo. The residue waspurified by column chromatography (10% MeOH/EtOAc) to afford the sixthintermediate compound as a white solid (0.619 g, 67%). mp 143-144° C.;¹H NMR (400 MHz, CDCl₃): δ 8.12-8.04 (brs, 1H), 7.67 (d, 1H), 7.18-7.12(m, 2H), 7.00-6.92 (m, 1H), 6.58 (d, 1H), 5.64-5.50 (br s,1H), 4.24 (t,2H), 4.08 (d, 2H), 3.15-3.01 (m, 4H), 2.70-2.59 (m, 4H), 2.48 (t, 2H),1.85-1.64 (m, 4H), 1.43 (s, 9H), 1.35 (s, 9H). MS ES: m/z=608.22,610.17.

A seventh intermediate compound,3-Aminomethyl-6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-pyridin-2-ylamine,was produced as follows: A mixture of[6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-2-(2,2-dimethyl-propionylamino)-pyridin-3-ylmethyl]-carbamicacid tert-butyl ester (0.557 g, 0.91 mmol) in 2 N aqueous KOH (5 mL) andEtOH (20 mL) was refluxed for 5 hours. The reaction was not complete(judged by ¹H NMR), so an additional amount of 2 N KOH (5 mL) was addedand the resulting mixture was refluxed overnight. The mixture was cooledto RT, then diluted with water and extracted with EtOAc. The organicextracts were dried over Na₂SO₄, filtered and concentrated in vacuo toafford a brown oil, which was used in the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ: 7.20-7.10 (m, 3H), 7.00-6.92(m, 1H), 5.98 (s, 1H), 5.17-5.00 (br s, 2H), 4.82-4.71 (br s, 2H), 4.18(t, 2H), 4.14 (d, 2H), 3.19-2.97 (m, 4H), 2.78-2.50 (m, 4H), 2.45 (t,2H), 1.85-1.62 (m, 4H), 1.44 (s, 9H).

To a solution of crude(2-amino-6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-pyridin-3-ylmethyl)-carbamicacid tert-butyl ester in dioxane (15 mL) was added 3 N HCl (15 mL). Theresulting mixture was refluxed for 2 hours, cooled to RT, thenneutralized with saturated Na₂CO₃. The neutralized solution wasextracted with EtOAc and the organic extracts were washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo to afford thetitle compound as a brown oil (0.367 g, 94 % over two steps). ¹H NMR(400 MHz, CDCl₃): δ 7.21-7.10 (m, 3H), 7.00-6.91 (m, 1H), 6.00 (d, 1H),5.40-5.21 (br s, 2H), 4.12 (t, 2H), 3.82 (s, 2H), 3.71 (s, 2H),3.19-2.98 (m, 4H), 2.81-2.55 (m, 4H), 2.50 (t, 2H), 1.91-1.43 (m, 4H).MS ES: m/z=424.00, 425.99.

A mixture of3-aminomethyl-6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-pyridin-2-ylamine(0.260 9, 0.61 mmol) in THF (10 mL) was treated with 4-nitrophenylchloroformate (0.160 g, 0.79 mmol). The mixture was stirred at roomtemperature for 30 minutes, then cooled to 0° C. and treated with LDA(0.9 mL, 3.8 mmol, 2.0 M in heptane/THF/ethylbenzene). The brown mixturewas stirred at room temperature for 1 hour, then quenched with water andextracted with EtOAc. The organic extracts were washed with water andbrine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was purified by preparative thin layer chromatography (10%MeOH/EtOAc) to afford the title compound as a light yellow solid (0.071g, 25 %). mp 166-167° C.; 1H NMR (400 MHz, CDCl₃): δ 7.25 (s, 1H),7.19-7.14 (m, 2H), 7.14-7.09 (br s, 1H), 6.99-6.94 (m, 1H), 6.32 (d,1H), 5.57-5.51 (br s, 1H), 4.45 (s, 2H), 4.24 (t, 2H), 3.16-3.02 (m,4H), 2.75-2.58 (m, 4H), 2.49 (t, 2H), 1.84-1.64 (m, 4H). MS ES:m/z=450.03, 452.02.

EXAMPLE F2 Synthesis of7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

A first intermediate compound,N-{3-Azidomethyl-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-2-yl}-2,2-dimethyl-propionamide,was produced as follows: To a solution ofN-[3-azidomethyl-6-(4-oxo-butoxy)-pyridin-2-yl]-2,2-dimethyl-propionamidein DCE (250 mL) was added 1-naphthalen-1-yl-piperazine monohydrochloride(2.81 g, 11.30 mmol), Et₃N (2.00 g, 19.80 mmol) and NaBH(OAc)₃ (2.38 g,11.20 mmol). The mixture was stirred at room temperature for 1 hour,then quenched with water and saturated NaHCO₃. The mixture was extractedwith CH₂Cl₂ and the combined extracts were washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (1:19, Et₃N/EtOAc) to afford the firstintermediate compound as a brown oil (2.36 g, 59 %). ¹H NMR (400 MHz,CDCl₃): δ 8.26-8.17 (m, 1H), 7.85-7.80 (m, 1H), 7.64 (d, 1H), 7.60 (s,1H), 7.55 (d, 1H), 7.50-7.44 (m, 2H), 7.41 (t, 1H), 7.10 (d, 1H), 6.64(d, 1H), 4.31 (s, 2H), 4.28 (t, 2H), 3.25-3.05 (m, 4H), 2.90-2.62 (m,4H), 2.55 (t, 2H), 1.90-1.68 (m, 4H), 1.35 (s, 9H). MS ES: m/z=516.20.

A second intermediate compound,{2-(2,2-Dimethyl-propionylamino)-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-3-ylmethyl}-carbamicacid tert-butyl ester, was produced as follows: A mixture ofN-{3-azidomethyl-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-2-yl}-2,2-dimethyl-propionamide(2.36 g, 4.60 mmol) and di-tert-butyl dicarbonate (1.035 g, 4.74 mmol)in EtOH (80 mL) was treated with Palladium on charcoal (10 % wet, 1.254g). The mixture was shaken under 45 psi of H₂ for 3.5 hours. Thesuspension was filtered through Celite and the Celite pad was washedwith EtOH. The filtrate was concentrated in vacuo to afford the secondintermediate compound as a white solid (2.64 g, 97 %). mp 80-82° C. ¹HNMR (400 MHz, CDCl₃): δ 8.24-8.16 (m, 1H), 8.00 (br s, 1H), 7.86-7.80(m, 1H), 7.66 (d, 1H), 7.55 (d, 1H), 7.50-7.42 (m, 2H), 7.40 (t, 1H),7.10 (d, 1H), 6.59 (d, 1H), 5.45 (br s, 1H), 4.28 (t, 2H), 4.09 (d, 2H),3.25-3.05 (m, 4H), 2.85-2.60 (m, 4H), 2.60-2.50 (m, 2H), 1.89-1.60 (m,4H), 1.42 (s, 9H), 1.35 (s, 9H). MS ES: m/z=590.33.

A third intermediate compound,{2-Amino-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-3-ylmethyl}-carbamicacid tert-butyl ester, was produced as follows: A mixture of{2-(2,2-dimethyl-propionylamino)-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-3-ylmethyl}-carbamicacid tert-butyl ester (2.64 g, 4.48 mmol) in 2 N aqueous. KOH (40 mL)and EtOH (40 mL) was refluxed overnight. The mixture was cooled to RT,then diluted with water and extracted with EtOAc. The organic extractswere dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by column chromatography (2.5% Et₃N/EtOAc) to afford thethird intermediate compound as a white solid (1.30 g, 58 %). mp 67-68°C. ¹H NMR (400 MHz, CDCl₃): δ 8.42-8.30 (m, 1H), 7.85-7.60 (m, 1H), 7.55(d, 1H), 7.51-7.40 (m, 2H), 7.39 (t, 1H), 7.16 (d,1H), 7.08 (d, 1H),6.00 (d,1H), 5.13-5.00 (br s, 2H), 4.85-4.70 (br s, 1H), 4.20 (t, 2H),4.14 (d, 2H), 3.28-3.04 (m, 4H), 2.90-2.62 (m, 4H), 2.54 (t, 2H),1.88-1.66 (m, 4H), 1.54 (s, 9H). MS ES: m/z=506.19.

A fourth intermediate compound,3-Aminomethyl-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-2-ylamine,was produced as follows: To a solution of{2-amino-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-3-ylmethyl}-carbamicacid tert-butyl ester (1.17 g, 2.31 mmol) in dioxane (10 mL) was added 3N HCl (10 mL). The resulting mixture was refluxed for 1 hour, cooled toRT, then neutralized with saturated Na₂CO₃. The neutralized solution wasextracted with EtOAc and the organic extracts were washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo to afford thefourth intermediate compound as a brown oil (0.92 g, 98 %). ¹H NMR (400MHz, CDCl₃): δ 8.22-8.15 (m, 1H), 7.85-7.78 (m, 1H), 7.55 (d, 1H),7.50-7.40 (m, 2H), 7.40 (t,1H), 7.18 (d, 1H), 7.09 (d, 1H), 6.00 (d,1H), 5.30 (br s, 2H), 4.20 (t, 2H), 3.79 (s, 2H), 3.71 (s, 2H), 3.28-3.06 (m, 4H), 2.96-2.64 (m, 4H), 2.56 (t, 2H), 1.88-1.68 (m, 4H). MSES: m/z=406.10.

A mixture of3-aminomethyl-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-2-ylamine(0.92 g, 2.27 mmol) in THF (25 mL) was treated with phenyl chloroformate(0.40 mL, 3.18 mmol) followed by Et₃N (0.46 g, 4.54 mmol). The mixturewas stirred at room temperature for 1 hour, then cooled to 0 ° C. andtreated with LDA (5.6 mL, 11.20 mmol, 2.0 M inheptane/THF/ethylbenzene). The brown mixture was stirred at roomtemperature for 1 hour, then quenched with water and extracted withEtOAc. The organic extracts were washed with water, and brine, driedover Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by column chromatography (2.5% Et₃N/EtOAc) to afford the titlecompound as a light yellow solid (0.204 g, 21 %). mp 136-138; ¹H NMR(400 MHz, CDCl₃): δ 8.24-8.16 (m, 1H), 7.85-7.78 (m, 1H), 7.55 (d, 1H),7.50-7.42 (m, 2H), 7.40 (t, 1H), 7.25 (d, 1H), 7.09 (d, 1H), 6.84 (brs,1H), 6.34 (d, 1H), 5.05 (br s, 1H), 4.48 (s, 2H), 4.45 (t, 2H),3.30-2.05 (m, 4H), 2.93-2.60 (m, 4H), 2.55 (t, 2H), 1.90-1.70 (m, 4H).MS ES: m/z=432.11.

EXAMPLE F3 Synthesis of7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

A first intermediate compound,2-Amino-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridine-3-carbaldehyde,was produced as follows: A mixture ofN-{3-formyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,2-dimethyl-propionamide(9.8 g, 25.9 mmol), 2 N KOH (35 mL) and EtOH (40 mL) was heated at 80°C. for 2 h. Ethanol was removed under reduced pressure and the residuewas extracted with EtOAc (3×100 mL). The combined organic phases werewashed with H₂O (40 mL) and brine (40 mL), dried over Na₂SO₄, andconcentrated to give the first intermediate compound as an oil which wasused in the next step without further purification. ¹H NMR (400 MHz,CDCl3): δ 9.70 (s, 1H), 7.62 (d, 1H), 6.17 (d, 1H), 4.60 (m, 1H), 4.40(m, 2H), 3.90 (m, 2H), 3.50 (m, 2H), 2.00-1.50 (m, 10H).

A second intermediate compound,7-[4-(Tetrahydro-pyran-2-yloxy)-butoxy]-1H-pyrido[2,3-d]pyrimidin-2-one,was produced as follows: To a solution of2-amino-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridine-3-carbaldehydeobtained in the last step in CH₂Cl₂ (50 mL) was added trichloroacetylisocyanate (5.85 g, 31.08 mmol) dropwise. After the addition was over,the mixture was stirred at room temperature for 1 h. To this mixture,MeOH (50 mL) and 1 N NaOH (40 mL) were added successively. The mixturethus obtained was kept stirring at room temperature for another 1 h. Thesolvent was then removed under reduced pressure and the residue wasextracted with CH₂Cl₂ (3×100 mL). The combined organic phases werewashed with brine, dried and concentrated. The residue was crystallizedfrom ether to give the second intermediate compound (6.6 g, 79% in twosteps) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.00 (s,1H), 8.00 (d, 1H), 6.60 (d, 1H), 4.60 (m, 1H), 4.40 (m, 2H), 3.70 (m,2H), 3,40 (m, 2H), 1.90 -1.30 (m, 10H).

A third intermediate,7-(4-Hydroxy-butoxy)-1H-pyrido[2,3-d]pyrimidin-2-one, was produced asfollows: A mixture of7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-1H-pyrido[2,3-d]pyrimidin-2-one(4.9 g, 15 mmol), MeOH (30 mL), THF (15 mL) and 3 N HCl (7.5 mL) wasstirred at room temperature for 1 h. The mixture was concentrated underreduced pressure. The residue was dissolved in H₂O (30 mL) andneutralized carefully with saturated NaHCO₃. The mixture was extractedwith THF (5×100 mL). The combined organic phases were washed with brine,dried and concentrated to give the third intermediate compound (3.3 g,90%) which was used in the next step without further purification. ¹HNMR (400 MHz, DMSO-d₆): δ 9.03 (s,1H), 8.17 (d,1H), 6.67 (d, 1H), 4.50(m, 1H), 4.40 (m, 2H), 3.50 (m, 3H), 1.80 (m, 2H), 1.55 (m, 2H).

A fourth intermediate compound,4-(2-Oxo-1,2-dihydro-pyrido[2,3-d]pyrimidin-7-yloxy)-butyraldehyde, wasproduced as follows: A mixture of7-(4-hydroxy-butoxy)-1H-pyrido[2,3-d]pyrimidin-2-one (0.512 g, 2.18mmol) and IBX (1.9 g, 6.6 mmol) in CH₃CN (40 mL) was heated at 87° C.for 7 h. It was cooled to RT, diluted with EtOAc (80 mL) and filtered.The pad was washed thoroughly with EtOAc. The combined filtrate wasconcentrated to give the fourth intermediate compound as a solid whichwas contaminated with some byproduct from the reaction. This solid wasused in the next step without further purification. ¹H NMR (400 MHz,DMSO-d₆): δ 12.18 (s, 1H), 9.77 (s, 1H), 8.20 (d, 1H), 6.70 (d, 1H),4.40 (m, 2H), 2.70 (m, 2H), 2.00 (m, 2H).

To a mixture of4-(2-oxo-1,2-dihydro-pyrido[2,3-pyrimidin-7-yloxy)-butyraldehyde,1-indan-4-yl-piperazine (0.581 g, 2.44 mmol), Et₃N (1.70 mL, 12.2 mmol)in 1-methyl-2-pyrrolidinone (20 mL) was added NaBH(OAc)₃ (0.65 g, 3.05mmol) in portions over 20 mim. After the addition was over, the mixturewas left stirring overnight. After quenching with H₂O (50 mL), thereaction mixture was extracted with CH₂Cl₂ (3×100 mL). The combinedorganic phases were washed with brine (100 mL), dried and concentrated.The residue was purified by chromatography on silica gel to give a gum(350 mg). To a solution of this gum in THF (6 mL) and MeOH (2 mL) wasadded NaBH₄ (63 mg) in portions. After the addition was over, themixture was kept stirring overnight. The reaction was quenched with H₂O.The mixture was extracted with CH₂Cl₂ (3×50 mL). The combined organicphases were dried over Na₂SO₄ and concentrated. The residue was purifiedby chromatography on silica gel to give a semi-solid which was convertedto its HCl salt by treating with 1 equivalent of 1 N HCl in a mixedsolvent of THF and Et₂O to give the title compound (176 mg) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.2 (s, 1H), 9.30 (s, 1H), 7.40 (d,1H), 7.10 (t, 1H), 6.95 (m, 2H), 6.77 (d, 1H), 6.30 (d, 1H), 4.25 (m,4H), 4.00 (m, 2H), 3.60 (m, 2H), 3.30 -3.00 (m, 6H), 2.80 (m, 4H), 2.00-1.70 (m, 6H).

EXAMPLE F4 Synthesis of7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

The procedure from Example F3 was followed using1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to give the titlecompound. ¹H-NMR (400 MHz, DMSO-d₆): δ 10.20 (s, 1H), 9.22 (s, 1H), 7.40(d, 1H), 7.10 (m, 1H), 6.95 (s, 1H), 6.85 (m 2H), 6.30 (d, 1H), 4.30 (m,4H), 3.70 -3.00 (m, 1OH), 2.80 -2.60 (m, 4H), 1.90-1.60 (m, 8H).

EXAMPLE F5 Synthesis of7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

The procedure from Example F3 was followed using1-(7-fluoro-naphthalen-1-yl)-piperazine to give the title compound. ¹HNMR (400 MHz, DMSO-d₆): δ 9.25 (s, 1H), 8.00 (m, 1H), 7.80 (m, 1H), 7.75(m, 1H), 7.40 (m, 3H), 7.20 (d, 1H), 6.95 (s, 1H), 6.30 (d, 1H), 4.23(m, 4H), 3.70-3.10 (m, 10H), 1.90 -1.70 (m, 4H).

EXAMPLE F6 Synthesis of8-{4-[4-(2-Oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-7-yloxy)-butyl]-piperazin-1-yl}-naphthalene-2-carbonitrile

The procedure from Example F3 was followed using8-piperazin-1-yl-naphthalene-2-carbonitrile to give the title compound.¹H NMR (400 MHz, DMSO-d₆): 9.25 (s, 1H), 8.60 (s, 1H), 8.10 (d, 1H),7.80 (m, 1H), 7.70 (m, 1H), 7.45-7.30 (m, 2H), 6.90 (s, 1H), 6.30 (d,1H), 4.25 (m, 4H), 3.80 -3.10 (m, 1 OH), 1.90 -1.70 (m, 4H).

EXAMPLE F7 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-methyl-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

A first intermediate compound,N-[6-(4-Benzyloxy-butoxy)-3-formyl-pyridin-2-yl]-2,2-dimethyl-propionamide,was produced as follows: To a stirred solution of 4-benzyloxy-1-butanol(300 mg, 1.66 mmol) in DMF (5 mL) at 0° C. was added NaH (50 mg, 2.08mmol). The resulting grey slurry was stirred at 0 ° C. for 15 minutesand N-(6-chloro-3-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (200mg, 0.83 mmol) was added portionwise. The mixture became a light orangecolor and bubbles were evolved. The orange mixture was allowed to warmto room temperature over 1 hour. Water (10 mL) was added and the mixturewas diluted with EtOAc (20 mL). The organic layer was separated, washedwith water (2×10 mL) and brine (20 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residual oil was purified by columnchromatography (3:1, hexane/EtOAc) to yield the first intermediatecompound as a clear oil (266 mg, 83%). ¹H NMR (400 MHz, CDCl₃) δ 11.55(s, 1H), 9.75 (s, 1H), 7.80 (d, 1H), 7.40-7.20 (m, 5H), 6.44 (d, 1H),4.60-4.44 (m, 4H), 3.50 (t, 2H), 1.95-1.70 (m, 4H), 1.36 (s, 9H).

A second intermediate compound,N-[6-(4-Benzyloxy-butoxy)-3-methylaminomethyl-pyridin-2-yl]-2,2-dimethyl-propionamide,was produced as follows: To a stirred solution ofN-[6-(4-benzyloxy-butoxy)-3-formyl-pyridin-2-yl]-2,2-dimethyl-propionamide(1.40 g, 3.65 mmol) in EtOH (20 mL) at room temperature was addedmethylamine monohydrochloride (295 mg, 4.37 mmol) and Et₃N (443 mg, 0.61mL, 4.37 mmol). The mixture was stirred for 24 hours and then cooled to0° C. NaBH₄ (138 mg, 3.65 mmol) was added and the mixture was warmed toroom temperature over 1 hour, then heated at 50° C. for 3 hours. Themixture was cooled to RT, water (20 mL) was added, and the mixture wasextracted with EtOAc (30 mL). The organic layer was separated, washedwith water (20 mL) and brine (20 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuo. The impure oil was purified by columnchromatography (5% MeOH/CH₂Cl₂) to yield the second intermediatecompound as a clear oil (1.22 g, 84%). ¹H NMR (400 MHz, CDCl₃) δ 10.55(s, 1H), 7.38-7.22 (m, 6 H), 6.39 (d, 1H), 4.46 (s, 2H), 4.38 (t, 2H),3.64 (s, 2H), 3.53 (t, 2H), 2.42 (s, 3H), 1.90-1.75 (m, 4H), 1.58 (brs,1H), 1.36 (s, 9H).

A third intermediate compound,[6-(4-Benzyloxy-butoxy)-2-(2,2-dimethyl-propionylamino)-pyridin-3-ylmethyl]-methyl-carbamicacid tert-butyl ester, was produced as follows:N-[6-(4-Benzyloxy-butoxy)-3-methylaminomethyl-pyridin-2-yl]-2,2-dimethyl-propionamide(1.22 g, 3.06 mmol) was dissolved in MeOH (20 mL) and di-tert-butyldicarbonate (701 mg, 3.21 mmol) was added. The mixture was stirred atroom temperature overnight and water (10 mL) was added. The mixture wasextracted with EtOAc (20 mL). The organic layer was washed with water(20 mL) and brine (20 mL), dried over Na₂SO₄, filtered and concentratedin vacuo to yield the third intermediate compound as a clear oil (1.48g, 97%). ¹H NMR (200 MHz, DMSO-d₆) δ 9.55 (s, 1H), 7.44 (d, 1H),7.40-7.20 (m, 5H), 6.72 (d, 1H), 4.48 (s, 2H), 4.25 (t, 2H), 4.15 (s,2H), 3.50 (t, 2), 2.70 (s, 3H), 1.90-1.60 (m, 4H), 1.45 (s, 9H), 1.25(s, 9H).

A fourth intermediate compound,[2-(2,2-Dimethyl-propionylamino)-6-(4-hydroxy-butoxy)-pyridin-3-ylmethyl]-methyl-carbamicacid tert-butyl ester, was produced as follows:[6-(4-Benzyloxy-butoxy)-2-(2,2-dimethyl-propionylamino)-pyridin-3-ylmethyl]-methyl-carbamicacid tert-butyl ester (1.48 g, 2.96 mmol) was dissolved in MeOH (20 mL)and treated with 10% palladium on charcoal (400 mg). The mixture wasshaken under an atmosphere of H₂ (45 psi) for 3 hours, filtered throughcelite and the celite was washed with EtOAc (2×20 mL). The filtrate wasconcentrated in vacuo to yield the fourth intermediate compound as aclear oil (1.21 g, 99%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (s, 1H), 7.42(d, 1H), 6.68 (d, 1H), 4.42 (t, 1H), 4.21 (t, 2H), 4.15 (s, 2H),3.44-3.41 (m, 2H), 2.70 (s, 3H), 1.80-1.70 (m, 2H), 1.60-1.54 (m, 2H),1.40 (s, 9H), 1.20 (s, 9H).

A fifth intermediate compound,[6-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-2-(2,2-dimethyl-propionylamino)-pyridin-3-ylmethyl]-methyl-carbamicacid tert-butyl ester, was produced as follows: To a stirred solution ofDess-Martin periodinane (926 mg, 2.18 mmol) in CH₂Cl₂ (20 mL) was added[2-(2,2-dimethyl-propionylamino)-6-(4-hydroxy-butoxy)-pyridin-3-ylmethyl]-methyl-carbamicacid tert-butyl ester (746 mg, 1.82 mmol) in CH₂Cl₂ (3 mL). The mixturewas stirred at room temperature for 3.5 hours, then poured into asolution of saturated NaHCO₃ (20 mL) containing Na₂S₂O₃ (2.01 g, 12.7mmol). The biphasic mixture was stirred vigorously for 15 minutes andthe organic layer was separated. The organic layer was washed withsaturated NaHCO₃ (20 mL) and brine (20 mL), dried over Na₂SO₄, filteredand concentrated in vacuo to yield the crude aldehyde (920 mg, 99%). Thealdehyde (920 mg, 1.82 mmol) was dissolved in 1,2-dichloroethane (20 mL)and 1-(2,3-dichlorophenyl) piperazine monohydrochloride (536 mg, 2.00mmol), Et3N (553 mg, 0.76 mL, 5.46 mmol), and NaBH(OAc)₃ (540 mg, 2.55mmol) were added. The mixture was stirred at room temperature for 3hours and water (10 mL) was added. The organic layer was washed withwater (20 mL) and brine (20 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude oil was purified by columnchromatography (5% MeOH/CH₂Cl₂) to yield the fifth intermediate compoundas a foam (686 mg, 61%). mp 57-59° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.56(s, 1H), 7.44 (d, 1H), 7.38-7.25 (m, 2H), 7.18-7.14 (m, 1H), 6.78 (d,1H), 4.24 (t, 2H), 4.15 (s, 2H), 3.00-2.95 (m, 4H), 2.64 (s, 3H),2.60-2.56 (m, 4H), 2.39 (t, 2H), 1.80-1.75 (m, 2H), 1.63-1.55 (m, 2H),1.40 (s, 9H), 1.20 (s, 9H).

A sixth intermediate compound,6-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-methylaminomethyl-pyridin-2-ylamine,was produced as follows:

[6-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-2-(2,2-dimethyl-propionylamino)-pyridin-3-ylmethyl]-methyl-carbamicacid tert-butyl ester (686 mg, 1.11 mmol) was dissolved in dioxane (4mL) and 3 N HCl (4 mL) was added. The solution was heated at 60° C. for15 hours. The solution was cooled to room temperature and neutralizedwith saturated Na₂CO₃. The mixture was diluted with water (20 mL) andEtOAc (20 mL). The organic layer was washed with water (2×20 mL) andbrine (20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo toyield the sixth intermediate compound as a brown powder (458 mg, 95%).mp 119-121° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.03 (m, 3H), 7.00-6.95(m, 1H), 5.97 (d, 1H), 5.20 (br s, 2H), 4.18 (t, 2H), 3.65 (s, 2H), 3.25(br s, 1H), 3.15-3.00 (m, 4H), 2.80-2.58 (m, 4H), 2.45 (t, 2H), 2.40 (s,3H), 1.83-1.63 (m, 4H).

To a stirred solution of6-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3-methylaminomethyl-pyridin-2-ylamine(203 mg, 0.47 mmol) in THF (10 mL) at 0° C. was added 4-nitrobenzylchloroformate (105 mg, 0.49 mmol). The mixture was stirred at 0° C. for45 minutes and LDA (1.16 mL, 2.32 mmol, 2.0 M solution inheptane/THF/ethylbenzene) was added dropwise. The mixture was stirredfor 1.5 hours at 0° C. and then poured over ice. EtOAc (30 mL) was addedto the quenched mixture and the organic layer was separated. The organiclayer was washed with water (20 mL) and brine (20 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude oil was purifiedby preparative TLC (6% MeOH/EtOAc) to yield the title compound as alight orange foam (66 mg, 31%). ¹H NMR (400 MHz, CDCl3) δ 7.22 (d, 1H),7.19-7.10 (m, 2H), 7.00-6.92 (m, 1H), 6.76 (s, 1H), 6.34 (d, 1H), 4.38(s, 2H), 4.22 (t, 2H), 3.14-3.00 (m, 4H), 3.00 (s, 3H), 2.77-2.58 (m,4H), 2.44 (t, 2H), 1.83-1.60 (m, 4H).

EXAMPLE F8 Synthesis of3-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

A first intermediate compound,{2-(2,2-Dimethyl-propionylamino)-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-3-ylmethyl}-methyl-carbamicacid tert-butyl ester, was produced as follows: To a stirred solution ofDess-Martin periodinane (3.10 g, 7.32 mmol) in CH₂Cl₂ (40 mL) was added[2-(2,2-dimethyl-propionylamino)-6-(4-hydroxy-butoxy)-pyridin-3-ylmethyl]-methyl-carbamicacid tert-butyl ester (2.00 g, 4.88 mmol) in CH₂Cl₂ (5 mL). The mixturewas stirred at room temperature for 3.5 hours and then poured into asolution of saturated NaHCO₃ (40 mL) containing Na₂S₂O₃ (5.40 g, 34.2mmol). The biphasic mixture was stirred vigorously for 20 minutes andthe organic layer was separated, washed with saturated NaHCO₃ (30 mL)and brine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuoto yield the crude aldehyde (1.95 g, 99%). The aldehyde (1.95 g, 4.88mmol) was dissolved in 1,2-dichloroethane (40 mL) and1-naphthalen-1-yl-piperazine monohydrochloride (1.34 g, 5.39 mmol), Et₃N(1.49 g, 2.05 mL, 5.46 mmol), and NaBH(OAc)₃ (1.45 g, 6.86 mmol) wereadded. The mixture was stirred at room temperature for 3 hours and water(20 mL) was added. The organic layer was washed with water (30 mL) andbrine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.The crude oil was purified by column chromatography (5% MeOH/CH₂Cl₂) toyield the first intermediate compound as a foam (1.39 g, 47%). mp 69-71°C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.58 (s, 1H), 8.15 (d, 1H), 7.85 (d,1H), 7.60 (d, 1H), 7.56-7.40 (m, 4H), 7.10 (d, 1H), 6.77 (d, 1H), 4.22(t, 2H), 4.10 (s, 2H), 3.08-2.98 (m, 4H), 2.70 (s, 3H), 2.70-2.58 (m,4H), 2.45 (t, 2H), 1.85-1.70 (m, 2H), 1.70-1.58 (m, 2H), 1.40 (s, 9H),1.20 (s, 9H).

A second intermediate compound,3-Methylaminomethyl-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-2-ylamine,was produced as follows:{2-(2,2-Dimethyl-propionylamino)-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-3-ylmethyl}-methyl-carbamicacid tert-butyl ester (1.39 g, 3.31 mmol) was dissolved in dioxane (6mL) and 3 N HCl (6 mL) was added. The solution was heated at 60° C. for8 hours. The solution was cooled to room temperature and neutralizedwith saturated Na₂CO₃. The mixture was diluted with water (30 mL) andEtOAc (30 mL). The organic layer was washed with water (2×30 mL) andbrine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo toyield the second intermediate compound as a brown oil (709 mg, 73%). ¹HNMR (400 MHz, CDCl₃) δ 8.20 (d, 1H), 7.80 (d, 1H), 7.60-7.40 (m, 4H),7.20 (d, 1H), 7.10 (d, 1H), 6.00 (d, 1H), 5.40 (s, 2H), 4.20 (t, 2H),3.60 (s, 2H), 3.24-3.00 (m, 4H), 2.90-2.60 (m, 4H), 2.57 (t, 2H), 2.40(s, 3H), 1.85-1.65 (m, 4H), 1.44 (s, 1H).

3-Methylaminomethyl-6-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-pyridin-2-ylamine(709 mg, 1.69 mmol) was dissolved in THF (10 mL) and cooled to 0° C.Phenyl chloroformate (291 mg, 0.23 mL, 1.86 mmol) was added dropwisefollowed by Et₃N (342 mg, 0.47 mL, 3.38 mmol). The mixture was allowedto warm to room temperature for 45 minutes. Water (20 mL) and EtOAc (20mL) were added. The organic layer was separated, washed with water (2×20mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated invacuo to give a yellow foam (850 mg, 93%). ¹H NMR (400 MHz, CDCl₃) δ8.23-8.18 (m, 1H), 7.81 (d, 1H), 7.60-7.04 (m, 11H), 6.02 (d, 1H), 5.24(s, 2H), 4.38 (s, 2H), 4.20 (t, 2H), 3.24-3.00 (m, 4H), 2.99 (s, 3H),2.95-2.64 (m, 4H), 2.60-2.50 (m, 2H), 1.90-1.70 (m, 4H).

The foam (850 mg, 1.57 mmol) was dissolved in THF (20 mL) and thesolution was cooled to 0° C. LDA (3.94 mL, 7.89 mmol, 2.0 M solution inheptane/THF/ethylbenzene) was added dropwise and the mixture became adark orange color. The mixture was allowed to warm to room temperatureover 1 hour and water (10 mL) and EtOAc (20 mL) were added. The organiclayer was separated, washed with water (2×20 mL) and brine (20 mL),dried over Na₂SO₄, filtered and concentrated in vacuo. The residual oilwas purified by column chromatography (6% MeOH/EtOAc) to yield the titlecompound as a light yellow powder (308 mg, 41%). mp 180-182° C.; ¹H NMR(400 MHz, CDCl₃) δ 8.20 (d, 1H), 7.82 (d, 1H), 7.60-7.40 (m, 4H),7.23-7.20 (m, 1H), 7.10 (d, 1H), 6.75 (s, 1H), 6.30 (d, 1H), 4.39 (s,2H), 4.23 (t, 2H), 3.24 (m, 4H), 3.02 (s, 3H), 2.84-2.60 (m, 4H),2.80-2.70 (m, 2H), 1.85-1.64 (m, 4H).

EXAMPLE F9 Synthesis of7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-4,4-dimethyl-1,4-dihydro-pyrido[2,3-d][1,3]oxazin-2-one

A first intermediate compound,N-[3-Acetyl-6-(5-chloro-pent-1-enyl)-pyridin-2-yl]-2,2-dimethyl-propionamide,was produced as follows: To a solution ofN-(3-acetyl-6-chloro-pyridin-2-yl)-2,2-dimethyl-propionamide (7.0 g,27.5 mmol) in DME (110 mL) purged and degassed with N₂ was addedPd(Ph₃P)₄ (953 mg, 0.83 mmol, 3 mol%, Strem). 5-Chloro-1-pentenylboronic acid (6.12 g, 41.2 mmol, 1.5 equiv) was added followed by 2MNa₂CO₃ (6.12 g, 57.8 mmol in 28 mL of H₂O). The mixture was refluxedovernight. The reaction was concentrated and then diluted with THF (100mL) and sonicated for 3 min. A white sticky precipitate formed. Themixture was filtered and washed with THF. The filtrate was concentratedand absorbed onto SiO₂. Purification by liquid chromatography (20-25%EtOAc/Hexanes) gave the product as a yellow solid. Recrystallizationfrom Et₂O/Hexanes gave the first intermediate compound as a pale yellowcrystalline solid (6.49 g, 20.1 mmol, 73%). MS: APCl: M+1: 323.2 (ExactMass: 322.14).

A second intermediate compound,N-(3-Acetyl-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-pyridin-2-yl)-2,2-dimethyl-propionamid,was produced as follows: To a mixture ofN-[3-acetyl-6-(5-chloro-pent-1-enyl)-pyridin-2-yl]-2,2-dimethyl-propionamide(6.34 g, 19.7 mmol) and 2,3-dichlorophenylpiperazine hydrochloride (6.35g, 23.75 mmol, 1.2 equiv) in CH₃CN (100 mL) was added K₂CO₃ (8.2 g, 59.4mmol, 3 equiv) followed by Kl (332 mg, 2 mmol, 0.1 equiv). The mixturewas refluxed for 2 days. H₂O was added to dissolve the salts and themixture was extracted with EtOAc. The organic layer was washed withsaturated NaHCO₃ and brine, dried over Na₂SO₄ and concentrated to give adark brown oil. Purification by liquid chromatography (5% EtOAc/CH₂Cl₂to 4% MeOH/CH₂Cl₂) gave a light brown foam (5.0 g). Recrystallizationfrom CH₃CN gave the second intermediate compound as a light tan solid(2.45 g, 4.73 mmol, 24%). The filtrate was concentrated and purified byliquid chromatography (3-4% MeOH/CH₂Cl₂) to give additional product as ayellow foam (1.27 g, 2.45 mmol, 12%). MS: APCl: M+1: 517.1 (Exact Mass:516.21).

A third intermediate compound,N-(3-Acetyl-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pentyl}-pyridin-2-yl)-2,2-dimethyl-propionamide,was produced as follows:N-(3-Acetyl-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-pyridin-2-yl)-2,2-dimethyl-propionamide(2.40 g, 4.62 mmol) was hydrogenated using Ra-Ni (0.3 g) in 1:1 EtOH/THF(50 mL) for 2 h. The reaction was filtered and concentrated.Purification by liquid chromatography (4% MeOH/CH₂Cl₂) gave the thirdintermediate compound as a yellow oil (2.09 g, 4.02 mmol, 87%). MS:APCl: M+1: 519.2 (Exact Mass: 518.22).

A fourth intermediate compound,1-(2-Amino-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pentyl}-pyridin-3-yl)-ethanone,was produced as follows: A solution ofN-(3-acetyl-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pentyl}-pyridin-2-yl)-2,2-dimethyl-propionamide(2.08 g, 4.00 mmol) in 3N HCl (50 mL) was refluxed overnight. Thereaction was cooled to room temperature and a precipitate formed. Thesolid was collected by filtration, washed with H₂O and dried to give thetitle compound as a yellow solid (HCl salt, 1.15 g, 2.44 mmol, 61%). Thefiltrate was made basic with 6N NaOH and extracted with CH₂Cl₂ (4×). Theorganic layer was washed with brine, dried over Na₂SO₄ and concentratedto give additional fourth intermediate compound (582 mg, 1.34 mmol, 33%)which looked clean by NMR and was used in the next step withoutpurification. MS: APCl: M+1: 435.2 (Exact Mass: 434.16).

A fifth intermediate compound,2-(2-Amino-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pentyl}-pyridin-3-yl)-propan-2-ol,was produced as follows: To a solution of1-(2-amino-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pentyl}-pyridin-3-yl)-ethanone(575 mg, 1.32 mmol) in THF (8 mL) cooled to 0° C. was added MeMgBr (3Min Et₂O, 2.2 mL, 6.60 mmol, 5 equiv) slowly. The reaction was exothermicand turned orange and then a precipitate formed. The reaction wasstirred at 0° C. for 15 min and at room temperature for 2 h. Thereaction was quenched with careful addition of saturated NH₄Cl and H₂O.The mixture was extracted with EtOAc. The organic layer was washed withH₂O and brine, dried over Na₂SO₄ and concentrated. Purification byliquid chromatography (6% MeOH/CH₂Cl₂ with 1% NH₄OH) gave a whitecrystalline solid (490 mg, 1.09 mmol, 82%). MS: APCl: M+1: 451.2 (ExactMass: 450.20).

To a solution of2-(2-amino-6-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pentyl}-pyridin-3-yl)-propan-2-ol(442 mg, 0.98 mmol) in THF (4 mL) and toluene (1 mL) was added Et₃N(0.30 mL, 2.15 mmol, 2.2 equiv). The mixture was cooled to 0° C. andphosgene (20% in toluene, 0.65 mL, 1.3 mmol) was added. A precipitateformed. The reaction was stirred at 0° C. for 15 min and at roomtemperature for 2 h. MeOH was added to quench the excess phosgene.Saturated NaHCO₃ and H₂O were added and the mixture was extracted withEtOAc. The organic layer was washed with H₂O and brine, dried overNa₂SO₄ and concentrated. Purification by liquid chromatography (3.5%MeOH/CH₂Cl₂) gave the title compound as a white foam (411 mg, 0.861mmol, 88%). The foam was dissolved in Et₂O/CH₂Cl₂ and 1 M HCl in Et₂O(0.86 mL) was added. The resulting white precipitate was collected byfiltration, washed with Et₂O and dried to give a fluffy white solid (400mg). MS: APCl: M+1: 477.1 (Exact Mass: 476.17).

EXAMPLE G1 Synthesis of6-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one

A first intermediate compound,6-(5-Chloro-pent-1-enyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one, was producedas follows: To a solution of 6-bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one(2.0 g, 8.73 mmol, WO 02/056882) in DME (45 mL) was added5-chloro-pent-1-enyl-boronic acid (1.94 g, 13.09 mmol), followed byPd(PPh₃)₄ (0.252 g, 0.218 mmol) and 2M Na₂CO₃ (1.855 g in 8.7 mL H₂O).The reaction was refluxed for 14 hours. The reaction was cooled, andpartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated. Purification bychromatography on silica gel (0-40% EtOAc/Hexanes) gave the firstintermediate compound as a white solid (1.935 g, 88%). MS: APCl: M+1:253.1 (Exact Mass: 252.07).

A second intermediate compound,6-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one,was produced as follows: To a solution of6-(5-chloro-pent-1-enyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one (0.710 g,2.80 mmol) in CH₃CN (10 mL) was added 1-(2,3-dichloro-phenyl)-piperazine(0.974 g, 4.21 mmol), followed by potassium carbonate (0.77 g, 5.6 mmol)and potassium iodide (0.092 g, 0.56 mmol). The reaction was refluxed for14 hours. The reaction was cooled to room temperature and partitionedbetween EtOAc and H₂O. The organic layer was washed with saturatedNaHCO₃ and brine, dried over Na₂SO₄ and concentrated to give an oil.Purification by chromatography on silica gel (0-7% MeOH/EtOAc) affordedthe second intermediate compound as a white solid (0.903 g, 72%). MS:APCl: M+1: 447.1 (Exact Mass: 446.13).

6-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one(0.774 g, 1.73 mmol) was hydrogenated using Ra—Ni (0.25 g) in THF for 16hours. The reaction was filtered and concentrated to give an oil. Ethylacetate was added and the product crashed out. The precipitate wasfiltered and dried to give the title compound as a white solid (0.645 g,83%). MS: APCl: M+1: 449.1 (Exact Mass: 448.14).

EXAMPLE G2 Synthesis of6-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pentyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one

An intermediate compound,6-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pent-1-enyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one,was produced as follows: To a solution of6-(5-chloro-pent-1-enyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one (0.408 9,1.61 mmol) in CH₃CN (7 mL) was added1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine (0.523 g, 2.41 mmol),followed by potassium carbonate (0.445 g) and potassium iodide (0.053 g,0.322 mmol). The reaction was refluxed for 14 hours. The reaction wascooled to room temperature and partitioned between EtOAc and H₂O. Theorganic layer was washed with saturated NaHCO₃ and brine, dried overNa₂SO₄ and concentrated to give an oil. Purification by chromatographyon silica gel (0-5% MeOH/EtOAc) afforded the first intermediate compoundas a yellow solid (0.172 g, 72%). MS: APCl: M+1: 433.2 (Exact Mass:432.25).

6-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-pent-1-enyl}-4H-pyrido[3,2-b][1,4]oxazin-3-one(0.098 g, 0.226 mmol) was hydrogenated using Ra—Ni in THF for 16 hours.The reaction was filtered and concentrated to give an oil. Purificationby chromatography on silica gel (0-5% MeOH/EtOAc) afforded the titlecompound as a film (0.059 g, 61%). This was dissolved in Et₂O and 1M HClin Et₂O (1 equivalent) was added. The resulting precipitate was filteredand dried to give a white solid. MS: APCl: M+1: 435.5 (Exact Mass:434.27).

EXAMPLE G3 Synthesis of6-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one

A first intermediate compound, 6-Amino4H-pyrido[3,2-b][1,4]oxazin-3-one,was produced as follows: A mixture of6-nitro-4H-pyrido[3,2-b][1,4]oxazin-3-one (34.23 g, 0.1755 mol), 20%Pd-C (3.0 g, 50% H₂O) and DMF (1 L) was hydrogentated at 20 psi H₂pressure. After 2 h, uptake of H₂ ceased with 141 psi of H₂ beingabsorbed. The reaction mixture was filtered through a pad of Celite®,washing with DMF (500 mL). The filtrate was diluted with cold H₂O (2 L)to give a solid. The solid was collected, washed with H₂O, slurried inEtOH (150 mL), collected, washed with heptane and dried to give thefirst intermediate compound (23.60 g, 81%) as a gray-tan solid.

A second intermediate compound,6-Fluoro-4H-pyrido[3,2-b][1,4]oxazin-3-one, was produced as follows: A 1gallon Nalgene jar (with openings in the top for a N₂ inlet and additionof solids) was cooled in an ice/salt bath and hydrogen fluoride-pyridine(500 g) was added. With magnetic stirring and under a stream of N₂,6-amino-4H-pyrido[3,2-b][1,4]oxazin-3-one (88.48 g, 0.5362 mol, 1.0equiv) was added slowly portion-wise. When addition was complete, thered-brown mixture was stirred for 0.25 h to ensure complete solution.Sodium nitrite (44.40 g, 0.6435 mol, 1.2 equiv) was added cautiouslyportion-wise over 0.5 hr. Each addition was exothermic and accompaniedby the evolution of HF and N₂. When addition was complete the reactionmixture was stirred in the ice/salt bath for 1 h. The reaction wasquenched by the slow, careful addition of ice-cold H₂O (2 L). Theresulting solid was collected, washed with H₂O, resuspended in H₂O (3×1L), collected, washed with H₂O and dried on the filter for 1 h. Thesolid was washed with heptane and dried under a N₂ stream for 2 h. Finaldrying in a vacuum oven for 24 h at ˜40° C. gave the second intermediatecompound (69.03 g, 76%) as an orange-brown solid. Mp 179.9-181.2 °.

A third intermediate compound,6-(4-Benzyloxy-butoxy)-4H-pyrido[3,2-b][1,4]oxazin-3-one, was producedas follows: A solution of 4-benzyloxy-butan-1-ol l (34.31 g, 33.37 mL,190.3 mmol) and potassium t-butoxide (1M solution; 181 mL) in THF (60mL) was prepared and stirred at room temperature for 20 min. Asuspension of 6-fluoro-4H-pyrido[3,2-b][1,4]oxazin-3-one (8 g, 48 mmol)in THF (100 mL) was prepared, and the alcoholbase solution was added tothis solution via canula. The reaction was heated at reflux for 25hours. The reaction was quenched with saturated NH₄Cl and water. Thesolution was brought to a pH of 8 and extracted with ethyl acetate. Theorganic layer was washed with brine and concentrated to give a solid.Purification by SiO₂ chromatography (0-70% EtOAc/hexanes) gave the thirdintermediate compound as a white solid (6.6 g, 42%). MS: APCl: M+1:329.2 (Exact Mass: 328.14).

A fourth intermediate compound,6-(4-Hydroxy-butoxy)-4H-pyrido[3,2-b][1,4]oxazin-3-one, was produced asfollows: To a solution of6-(4-benzyloxy-butoxy)-4H-pyrido[3,2-b][1,4]oxazin-3-one (6.4 g, 19mmol) in MeOH/THF (100 mL) was added 20% Pd/C (1.5 g) and the mixturewas hydrogenated for 12 h. The reaction was filtered, concentrated andpurified by liquid chromatography (0-10% MeOH/CH₂Cl₂) to give the fourthintermediate compound as a white solid (4.3 g, 18 mmol, 93%). MS: APCl:M+1: 239.1 (Exact Mass: 238.10).

A fifth intermediate compound,4-(3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yloxy)-butyraldehyde,was produced as follows: To a suspension of6-(4-hydroxy-butoxy)-4H-pyrido[3,2-b][1,4]oxazin-3-one (4.3 g, 18.02mmol) in dichloroethane (30 mL) was added IBX (15 g, 54 mmol). Thismixture was heated at 80° C. for 5 hours. The reaction was cooled andstirred, and then filtered. The filter cake was washed with CH₂Cl₂ untilthe product was removed. The filtrate was concentrated to give a redoil, which was purified by SiO₂ chromatography (0-7% MeOH/CH₂Cl₂) togive the fifth intermediate compound as a red oil (3.90 g, 16.5 mmol,92%). MS: APCl: M+1: 237.1 (Exact Mass: 236.08).

To a solution of4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yloxy)-butyraldehyde(0.325 g, 1.37 mmol) in dichloroethane (6 mL) was added a solution of1-(2,3-dichloro-phenyl)-piperazine (0.318 g, 1.37 mmol) indichloroethane (3 mL) via cannula. The mixture was stirred for 20minutes at room temperature and NaBH(OAc)₃ (0.377 g, 1.78 mmol) wasadded. The reaction was stirred for 2.5 h and quenched with saturatedNaHCO₃ and water. The mixture was extracted with EtOAc and the organiclayer was washed with saturated NaHCO₃, water and brine, dried overNa₂SO₄ and concentrated. Purification by chromatography on silica gel(0-5% MeOH/CH₂Cl₂) gave a foam. Et₂O was added and product crashed out.The precipitate was filtered and dried to give the title compound as awhite solid (0.386 g, 0.854 mmol, 63%). MS: APCl: M+1: 451.1 (ExactMass: 450.12).

EXAMPLE G4 Synthesis of6-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-4H-pyrido[3,2-b][1,4]oxazin-3-one

The reductive amination procedure from Example G3 was followed using1-indan-4-yl-piperazine to give the title compound (0.24 g; 69%). MS:APCl: M+1: 423.3 (Exact Mass: 422.23).

EXAMPLE G5 Synthesis of6-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-4H-pyrido[3,2-b][1,4]oxazin-3-one

The reductive amination procedure from Example G3 was followed using1-naphthalen-1-yl-piperazine to give the title compound (0.24 g, 56%).MS: APCl: M+1: 433.1 (Exact Mass: 432.22).

EXAMPLE G6 Synthesis of6-{4-[4-(6-Methoxy-pyridin-2-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one

The reductive amination procedure from Example G3 was followed using1-(6-methoxy-pyridin-2-yl)-piperazine to give the title compound (0.21g, 62%). MS: APCl: M+1: 414.2 (Exact Mass: 413.21).

EXAMPLE G7 Synthesis of6-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one

The reductive amination procedure from Example G3 was followed using1-(7-fluoro-naphthalen-1-yl)-piperazine to give the title compound (0.31g, 64%). MS: APCl: M+1: 451.3 (Exact Mass: 450.21).

EXAMPLE G8 Synthesis of6-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one

The reductive amination procedure from Example G3 was followed using1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to give the titlecompound (0.23 g, 65%). MS: APCl: M+1: 437.3 (Exact Mass: 436.25).

EXAMPLE H1 Synthesis of2-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one

A first intermediate compound,2-Methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one, was produced asfollows: To a suspension of2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (5.0 g, 25.9 mmol) inCH₂Cl₂ (100 mL), CHCl₃ (50 mL) and MeOH (10 mL, the starting materialstill did not dissolve) was added the oxaziridine (8.11 g, 31.05 mmol,1.2 equiv) as a solid. The reaction became homogenous after 3 h and wasstirred overnight at RT. The reaction was concentrated and CH₂Cl₂/MeOHwas added to dissolve the residue. Much of the solid did not dissolve sothe mixture was filtered to give an off-white solid which was the firstintermediate compound (2.31 g, 11.04 mmol, 43%). MS: APCl: M+1: 210.1(Exact Mass: 209.03).

A second intermediate compound,2-[4-(Tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one,was produced as follows: To a solution of4-(tetrahydro-pyran-2-yloxy)-1-butanol (4.45 g, 25.3 mmol, 2.5 equiv) inTHF (20 mL) cooled to 0° C. was added 1M KOtBu in THF (25 mL, 25 mmol).The solution was stirred at 0° C. for 20 min and then added to asuspension of 2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (2.12 g,10.13 mmol) in DMF (30 mL) at RT. The reaction became homogenous and wasstirred at room temperature for 1 h. Saturated NH4Cl and H2O were addedto quench the reaction. The mixture was extracted with EtOAc. Theorganic layer was washed with H20 and brine, dried over Na2SO4 andconcentrated. Purification by liquid chromatography (70% EtOAc/Hexanesto 100% EtOAc) gave the second intermediate compound as a white solid(1.95 g, 6.11 mmol, 60%). MS: APCl: M+1: 320.2 (Exact Mass: 319.15).

A third intermediate compound,2-(4-Hydroxy-butoxy)-8H-pyrido[2,3-d]pyrimidin-7-one, was produced asfollows: To a suspension of2-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one(1.95 g, 6.11 mmol) in EtOH (30 mL) and CH₂Cl₂ (2 mL, added to helpdissolve the starting material) was added PPTS (151 mg, 0.6 mmol). Thesolution was stirred overnight at room temperature and then heated at60° C. for 5 h. The reaction was concentrated to give a white solid.Purification by liquid chromatography (6% MeOH/CH2Cl2) gave the thirdintermediate compound as a white solid (1.22 g, 5.19 mmol, 85%). MS:APCl: M+1: 236.1 (Exact Mass: 235.10).

A fourth intermediate compound,4-(7-Oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde, wasproduced as follows: To a solution of2-(4-hydroxy-butoxy)-8H-pyrido[2,3-d]pyrimidin-7-one (251 mg, 1.07 mmol)in DMSO (3 mL) was added a solution of IBX (597 mg, 2.13 mmol) in DMSO(7 mL, 0.3 M). The reaction was stirred at room temperature for 90 min,cooled to 0° C. and quenched with 5% NaHCO3. The mixture was extractedwith CH₂Cl₂ (4×). The organic layer was washed with 5% NaHCO3 and brine,dried over Na₂SO₄ and concentrated to give the fourth intermediatecompound as a white solid (171 mg, 0.733 mmol, 69%). MS: APCl: M+1:234.1 (Exact Mass: 233.08).

To a suspension of4-(7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde (235mg, 1.01 mmol) in dichloroethane (5 mL) was added1-(2,3-dichloro-phenyl)-piperazine hydrochloride (270 mg, 1.01 mmol)followed by Et3N (0.28 mL, 2.0 mmol, 2 equiv). After 10 min at RT,NaBH(OAc)3 (297 mg, 1.4 mmol) was added as a powder. The reaction wasstirred for 2 h at room temperature and quenched with saturated NaHCO3and H2O. The mixture was extracted with EtOAc (with a little MeOH tohelp dissolve the solids). The organic layer was washed with brine andconcentrated. Purification by liquid chromatography (5% MeOH/CH2Cl2 with1% NH4OH) gave the title compound as a white solid (375 mg, 0.836 mmol,83%). MS: APCl: M+1: 448.1 (Exact Mass: 447.12).

The pyrimidines of Examples H2 and H3 were synthesized in acombinatorial library format by reductive amination of the appropriatepiperazine starting materials with4-(7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde usingthe procedure outlined in Example H1.

EXAMPLE H2 Synthesis of2-{4-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as a white solid (223 mg, 0.510 mmol,59.4%). MS: APCl: M+1: 438.1 (Exact Mass: 437.24).

EXAMPLE H3 Synthesis of2-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as a white solid (270 mg, 0.643 mmol,75.1%). MS: APCl: M+1: 420.3 (Exact Mass: 419.23).

EXAMPLE H4 Synthesis of2-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one

Following the same procedure as in Example H12 and starting from2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (300 mg, 1.332 mmol,U.S. Pat. No. 6,498,163) and4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (416 mg, 1.465 mmol),the title compound was made as a solid (300 mg, 0.683 mmol, 51.3%). MS:APCl: M+1: 430.2 (Exact Mass: 429.22).

EXAMPLE H5 Synthesis of6-Fluoro-4-methyl-2-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one

Following the same procedure as in Example H12 and starting from6-fluoro-2-methanesulfonyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (300mg, 1.166 mmol, U.S. Pat. No.6,498,163) and4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (331 mg, 1.166 mmol),the title compound was made as a solid (323 mg, 0.684 mmol, 58.7%). MS:APCl: M+1: 462.1 (Exact Mass: 461.22).

EXAMPLE H6 Synthesis of2-{4-[4-(6-Isopropyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one

A first intermediate compound,2-Methanesulfonyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, was producedas follows: A solution of4-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (24 g, 0.1158mol, U.S. Pat. No. 6,498,163) in a mixture of CH₂Cl₂ (1.9 L) andmethanol (300 mL) is treated with m-chloroperbenzoic acid (103 g, 60%,0.345 mol) in portions at room temperature. The mixture is stirred for24 h, cooled to ˜5° C. and quenched with saturated sodium bicarbonatesolution. The solids are filtered, washed thoroughly with water followedby ether and dried in vacuum to give the first compound as a solid (10g, 0.042 mol, 36%). MS: APCl: M+1: 240.0 (Exact Mass: 239.04).

A second intermediate compound,4-Methyl-2-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one,was produced as follows: To a ice bath cooled solution of4-(tetrahydro-pyran-2-yloxy)-butan-1-ol (27.3 g, 0.1567 mol) in dry THF(125 mL) is added drop wise a solution of KOtBu (1M, 155 mL, 0.155 mol)in THF within 15 min. The mixture is then stirred at 0° C. for 2 h. Tothis mixture is added a suspension of2-methanesulfonyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (15 g, 0.0627mol) in DMF (225 mL) at room temperature within 15 min. The orange redcolored reaction mixture is stirred at room temperature for 1.5 h,cooled and quenched with saturated NH₄Cl solution (150 mL) and water (2L). The mixture is extracted with ethyl acetate (2×0.75 L) and theorganic layer is washed with brine (300 mL), dried over anhydrous sodiumsulfate, filtered through a small bed of silica gel eluting with 5%methanol in ethyl acetate (750 mL) and concentrated. The residue is thentriturated with hexane, filtered and dried to give the secondintermediate compound as a white solid (16.5 g, 0.0495 mol 78%). MS:APCl: M+1: 334.0 (Exact Mass: 333.17).

A third intermediate compound,2-(4-Hydroxy-butoxy)-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, wasproduced as follows: A mixture of4-methyl-2-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one(16.5 g, 0.049 mol) and PPTS (1.24 g, 0.0049 mol) in ethanol (250 mL)and CH₂Cl₂ (20 mL) is stirred at room temperature for 16 h, followed byheating at reflux (˜90° C.) for 3 h. The cloudy reaction mixture isevaporated under vacuum and the residue is triturated in hexane-ethylacetate (150 mL, 1:1) and dried to give the third intermediate compoundas a yellow powder (12.5 g, 0.049 mol, 100%). MS: APCl: M+1: 250.0(Exact Mass: 249.11).

A fourth intermediate compound,4-(4-Methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde,was produced as follows: A stirred solution of IBX (26 g, 0.092 mol) inDMSO (220 ml) is treated with2-(4-hydroxy-butoxy)-4-methyl-BH-pyrido[2,3-d]pyrimidin-7-one (11 g,0.0467 mol) portion wise while stirring at room temperature during 30min and the reaction is stirred at room temperature for an additional 2h. The mixture is cooled and treated with saturated NaHCO₃ (150 mL) andextracted with chloroform (4×0.5 L). The combined organic layer iswashed with brine/ice (2 ×), dried over Na₂SO₄, filtered andconcentrated. The residue is stirred with ether, filtered, washed withether and dried to give 6 g of the crude, which shows it to be amixture. The ether filtrate residue also shows some product, but mostlystarting material. The residue from the filtrate and the crude (11 g)are subjected to re-oxidation as above using fresh IBX (15.5 g, 0.055mol) in DMSO (150 mL), but stirred at 30° C. for 3 h. Workup as aboveyielded the fourth intermediate compound as an off-white powder (8.3 g,0.057 mol, 66.8%). MS: APCl: M+1: 248.0 (Exact Mass: 247.10).

4-(4-Methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde(74.2 mg, 0.3 mmol) and 1-(6-isopropyl-pyridin-2-yl)-piperazine (62.8mg, 0.306 mmol) were combined in methylene chloride and stirred in avial over sieves for 10 min. Sodium triacetoxyborohydride (89 mg, 0.42mmol) was added and the reaction was stirred overnight. The reaction wasquenched by slowly adding water and then the mixture was filtered. Theresidue was partitioned between CH₂Cl₂ and water and the organic layerwas concentrated. Purification by liquid chromatography (MPLC, gradientof 100% CH₂Cl₂ to 100% of a 10% MeOH in CH₂Cl₂ solution) gave the titlecompound as a low melting solid (55 mg, 0.126 mmol, 42%). MS: APCl: M+1:437.3 (Exact Mass: 436.26).

The pyrimidines of Examples H6-H11 were synthesized in combinatoriallibrary format by reductive amination of the appropriate piperazinestarting materials with4-(4-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehydefollowing the procedure outlined in Example H7.

EXAMPLE H7 Synthesis of2-{4-[4-(6-Ethyl-pyridin-2-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as a low melting solid (87 mg, 0.206mmol, 68.6%). MS: APCl: M+1: 423.3 (Exact Mass: 422.24).

EXAMPLE H8 Synthesis of2-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as a white powder (66 mg, 0.152 mmol,50.74%). MS: APCl: M+1: 434.2 (Exact Mass: 433.25).

EXAMPLE H9 Synthesis of4-Methyl-2-{4-[4-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as a white powder (75 mg, 0.167 mmol,55.86%). MS: APCl: M+1: 448.3 (Exact Mass: 447.26).

EXAMPLE H10 Synthesis of2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido2,3-d]pyrimidin-7-one

The title compound was isolated as a solid (61 mg, 0.132 mmol, 44.06%).MS: APCl: M+1: 462.2 (Exact Mass: 461.22).

Example H11 Synthesis of2-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as a solid (43 mg, 0.09 mmol, 30.3%).MS: APCl: M+1:474.3 (Exact Mass: 473.24).

Example H12 Synthesis of4-Methyl-2-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one

2-Methanesulfonyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (300 mg,1.245 mmol, U.S. Pat. No. 6,498,163),4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (392 mg, 1.379 mmol) andsodium t-butoxide (362 mg, 3.76 mmol) were combined in a vial. Dioxane(10 mL) was added and the solution was stirred for 1 h. The reactionmixture was concentrated and then partitioned between ethyl acetate andwater. The organic layer was washed with water, dried over Na₂SO₄,filtered and concentrated. Purification by liquid chromatography (MPLC,gradient of 100% CH₂Cl₂ to 100% of 100:8:1 CH₂Cl₂:EtOH:NH₄OH solution)gave the title compound as a solid (220 mg, 0.485 mmol, 38%). MS: APCl:M+1:444.2 (Exact Mass: 443.23).

Example H13 Synthesis of2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4,8-dimethyl-8H-pyrido[2,3-d]pyrimidin-7-one

A first intermediate compound,2-Methanesulfonyl-4,8-dimethyl-8H-pyrido[2,3-d]pyrimidin-7-one, wasproduced as follows: A solution of4,8-dimethyl-2-methylthio-8-hydropyridino[2,3-d]pyrimidin-7-one (48.0 g,0.216 mol) in a mixture of CH₂Cl₂ (2.8 L) and methanol (410 mL) istreated with m-chloroperbenzoic acid (100 g, 57-86%) in portions at roomtemperature. The mixture is stirred for 24 h, filtered and the filtrateis concentrated. The residue is dissolved in chloroform, washed withsaturated NaHCO₃ (2×300 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude which upon purification by columnchromatography (EtOAc/Hexanes) gave the first intermediate compound aswhite solid (38 g, mmol, 0.150 mol, 69%). MS: APCl: M+1:254.0 (ExactMass: 253.05).

A second intermediate compound4,8-Dimethyl-2-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one,was produced as follows: To a solution of4-(tetrahydro-pyran-2-yloxy)-butan-1-ol (82.3 g, 0.472 mol) in dry THF(450 mL) cooled to 0° C. is added drop-wise a solution of KOtBu (1M inTHF, 473 mL, 0.472 mol) within 1 h. The mixture is stirred at 0° C. for1 h and then a solution of2-methanesulfonyl-4,8-dimethyl-8H-pyrido[2,3-d]pyrimidin-7-one (38 g,0.15 mol) in DMF (475 mL) is added at room temperature within 15 min.The mixture is stirred at room temperature for 1 h, cooled and quenchedwith saturated NH₄Cl (300 mL) followed by water (2L) and extracted withEtOAc (3×1 L). The organic layer is washed with brine (3×500 mL), driedover MgSO₄, filtered and concentrated. The residue is purified by columnchromatography (EtOAc/Hexane, 70%-100%) to afford the secondintermediate compound as an oil (24.6 g, 0.071 mol, 47.2%). MS: APCl:M+1:348.0 (Exact Mass: 347.18).

A third intermediate compound,2-(4-Hydroxy-butoxy)-4,8-dimethyl-8H-pyrido[2,3-d]pyrimidin-7-one, wasproduced as follows: A mixture of4,8-dimethyl-2-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one(24 g, 0.069 mol) and PPTS (1.9 g, 0.0075 mol) in ethanol (200 mL) isheated to ˜65° C. overnight. The mixture is evaporated under vacuum. Theresidue is dissolved in CH₂Cl₂ (500 mL), washed with water (3×100 mL),NaHCO₃solution (2×100 mL), dried over MgSO₄, filtered and evaporatedunder vacuum. The residue obtained is stirred in ether, filtered, washedwith ether and dried to give the third intermediate compound as anoff-white solid (9.5 g, 0.361 mol, 52.5%). MS: APCl: M+1:264.0 (ExactMass: 263.13).

A fourth intermediate compound,4-(4,8-Dimethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde,was produced as follows: A stirred solution of2-(4-hydroxy-butoxy)-4,8-dimethyl-8H-pyrido[2,3-d]pyrimidin-7-one (9.26g, 0.0351 mol) in DMSO (180 mL) is treated with IBX (19.7 g, 0.070 mol)and the mixture is stirred at room temperature for 1.5 h. The mixture iscooled to 0° C., treated with saturated NaHCO₃ (400 mL) and extractedwith CH₂Cl₂ (4×200 mL). The combined organic layer is washed with 15%NaHCO₃ brine/ice (2×100 mL), dried over Na₂SO₄, filtered andconcentrated. The residue obtained is stirred with ether, filtered,washed with ether and dried to give the fourth intermediate compound asa cream white solid (6.9 g, 0.026 mol, 75.2%). MS: APCl: M+1:262.0(Exact Mass: 261.11).

4-(4,8-dimethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde(78.4 mg, 0.30 mmol) and 1-(7-fluoro-naphthalen-1-yl)-piperazinetrifluoroacetic acid (105 mg, 0.306 mmol) were combined in methylenechloride and triethylamine (63 mg, 0.63 mmol) was added. The mixture wasstirred in a vial over sieves for 10 min. Sodium triacetoxyborohydride(89 mg, 0.420 mmol) was added and the reaction was stirred overnight.The reaction was quenched slowly with water and the mixture wasfiltered. The residue was partitioned between CH₂Cl₂ and water. Theorganic layer was washed with water and concentrated. Purification byliquid chromatography (MPLC, gradient of 100% CH₂Cl₂ to 100% of a 10%MeOH in CH₂Cl₂ solution) gave the title compound as awhite foam (89 mg,0.187 mmol, 62.4%). MS: APCl: M+1: 476.2 (Exact Mass: 475.24).

Example H14 Synthesis of2-{4-[4-(7-Methoxy-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4,8-dimethyl-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was prepared as described above using1-(7-methoxy-naphthalen-1-yl)-piperazine to give a pale yellow foam (91mg, 0.186 mmol, 62.2%). MS: APCl: M+1: 488.2 (Exact Mass: 487.26).

Example I1 Synthesis of7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A first intermediate compound, (4-Amino-6-chloro-pyridin-3-yl)-methanol,was produced as follows: To a suspension of LiAlH₄ (2.20 g, 58 mmol) inTHF (100 mL) was added a solution of 4-amino-6-chloro-nicotinic acidethyl ester (8.0g, 36.2 mmol) via cannula. After 90 minutes, H₂O (2.2mL) was added slowly and the mixture was stirred for 20 minutes. 3M NaOH(2.2 mL) was added, followed by H₂O (6.6 mL) and the mixture was stirredfor 1 hour. The precipitate was filtered. The organic layer was washedwith saturated NaHCO₃and brine, dried over Na₂SO₄ and concentrated togive the first intermediate compound as a yellow solid (6.39 g, 69%).MS: APCl: M+1: 159.1 (Exact Mass: 158.03).

A second intermediate compound,3-(4-Amino-6-chloro-pyridin-3-yl)-acrylic acid ethyl ester, was producedas follows: To a suspension of (4-amino-6-chloro-pyridin-3-yl)-methanol(6.39 g, 40.29 mmol) in CH₂Cl₂, was added barium manganate (17.55 g,68.49 mmol), followed by (carbethoxymethylene)triphenylphosphorane(19.71 g, 52.37 mmol). The reaction was refluxed for 5 hours and thenstirred at room temperature for 14hours. The reaction was filteredthrough Celite, washed with CH₂Cl₂ and the filtrate was concentrated.Et₂O was added and the mixture was stirred for 14 hours. The precipitate(Ph₃PO) was filtered off and the filtrate was concentrated. Purificationby liquid chromatography (30-50% EtOAc/Hexanes) gave the secondintermediate compound as a white solid (5.85 g, 64%). MS: APCl: M+1:227.2(Exact Mass: 226.05).

A third intermediate compound,3-(4-Amino-6-chloro-pyridin-3-yl)-propionic acid ethyl ester, wasproduced as follows: 3-(4-Amino-6-chloro-pyridin-3-yl)-acrylic acidethyl ester (2.51 g, 11.0 mmol) was hydrogenated using 5% Pd/BaSO₄in THF(100 mL) for 28 hours. The reaction was filtered and concentrated togive a yellow oil. Purification by liquid chromatography (20-40%EtOAc/Hexanes) afforded the third intermediate compound as a colorlessoil (1.191 g, 48%). MS: APCl: M+1: 229.0 (Exact Mass: 228.05).

A fourth intermediate compound,7-Chloro-3,4-dihydro-1H-[1,6]naphthyridin-2-one, was produced asfollows: To a solution of 3-(4-amino-6-chloro-pyridin-3-yl)-propionicacid ethyl ester (1.034 g, 4.53 mmol) in ethanol, was added DBU. Thereaction was heated to 70° C. and stirred for 20 hours. The reaction wascooled and concentrated. Purification by liquid chromatography (20-50%EtOAc/Hexanes) gave the fourth intermediate compound as a white solid(0.794 g, 96%). MS: APCl: M+1: 183.0 (Exact Mass: 182.02).

A fifth intermediate compound,7-(5-Chloro-pent-1-enyl)-3,4-dihydro-1H-[-[1,6]naphthyridin-2-one, wasproduced as follows: To a solution of7-chloro-3,4-dihydro-1H-[1,6]naphthyridin-2-one (0.908 g, 4.97 mmol) inDME (20 mL) was added 5-chloro-pent-1-enyl-boronic acid (1.475 g, 9.94mmol), followed by Pd(PPh₃)₄ (0.144 g, 0.124 mmol) and 2M Na₂CO₃ (1.053g in 5.0 mL H₂O). The reaction was refluxed for 14 hours. The reactionwas cooled, and partitioned between EtOAc and water. The organic layerwas washed with brine, dried over Na₂SO₄ and concentrated. Purificationby chromatography on silica gel (0-40% EtOAc/Hexanes) gave the fifthintermediate compound as a white solid (0.763 g, 61%). MS: APCl: M+1:253.1 (Exact Mass: 252.10).

A sixth intermediate compound,7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,6]naphthyridin-2-one,was produced as follows: To a solution of7-(5-chloro-pent-1-enyl)-3,4-dihydro-1H-[1,6]naphthyridin-2-one (0.72 g,2.87 mmol) in CH₃CN (10 mL) was added 1-(2,3-dichloro-phenyl)-piperazine(0.994 g, 4.30 mmol), followed by K₂CO₃ (0.793 g, 5.74 mmol) and KI(0.095 g, 0.574 mmol). The reaction was refluxed for 14 hours. Thereaction was cooled to room temperature and partitioned between EtOAcand H₂O. The organic layer was washed with saturated NaHCO₃ and brine,dried over Na₂SO₄ and concentrated to give an oil. Purification bychromatography on silica gel (10-40% MeOH/EtOAc) afforded the sixthintermediate compound as a white solid (0.903 g, 72%). MS: APCl: M+1:445.1(Exact Mass: 444.15).

7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,6]naphthyridin-2-one(0.417 g, 0.937 mmol) was hydrogenated using Ra—Ni (0.25 g) in THF for 2hours. The reaction was filtered and concentrated to give a white solid.EtOAc was added and the product crashed out. The precipitate wasfiltered and dried to give the title compound as a white solid (0.391 g,93%). MS: APCl: M+1: 447.2 (Exact Mass: 446.16).

Example I2 Synthesis of7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one

The first intermediate compound, 3-(4,6-Diamino-pyridin-3-yl)-acrylicacid ethyl ester, was produced as follows: A mixture of(carbethoxymethylene)triphenylphosphorane (436 g, 1.25 mol) and4,6-diaminopyridine-3-carbaldehyde (131.8 g, 0.96 mol) in 1,4-dioxane(2.0 L) was refluxed for 2.0 h. The mixture was cooled and filteredthrough silica gel (800 g) eluting with 0-10% MeOH/EtOAc. The filtratewas concentrated and the residue (˜580 g) was used in the next stepwithout further purification.

A second intermediate compound, 7-Amino-1H-[1,6]naphthyridin-2-one, wasproduced as follows: The residue obtained from the above procedure wasrefluxed in conc. HCl (1.5 L) for 1.5 h. The mixture was cooled anddiluted with water (2.5 L). At 35-40° C., the mixture was washed withEtOAc (3×). The aqueous layer was made basic with 50% NaOH to pH>10while cooling with a cold water bath. The resulting solid was collectedvia filtration, rinsed with water, methanol, and oven dried to affordthe second intermediate compound (106 g, 68% for two steps) as off-whitecrystals.

A third intermediate compound, 7-Fluoro-1H-[1,6]naphthyridin-2-one, wasproduced as follows: To a stirred mixture of HF-pyridine (660 g) and7-amino-1H-[1,6]naphthyridin-2-one (58 g, 0.36 mol) in a plastic bottlewas added NaNO₂ (39.7 g, 0.57 mol) in small portions over 30-40 minwhile cooled with a cold (˜10° C.) water bath in order to keep theinternal temperature at around RT. After the addition, the mixture wasfurther stirred at room temperature for 20 min before it was poured intowater (2.6 L) and stirred for 3.0 h. The resulting solid was collectedvia filtration, rinsed with water (2×), EtOAc-heptane (1:1, 2×), andoven dried to afford the third intermediate compound (48.6 g, 82%) aspale solid.

A fourth intermediate compound,7-(4-Benzyloxy-butoxy)-1H-[1,6]naphthyridin-2-one, was produced asfollows: A solution of 4-benzyloxy-butan-1-ol (35.98 g,199.6 mmol) andpotassium t-butoxide (21 g,188 mmol) in THF (60 mL) was prepared andstirred at room temperature for 20 min. A suspension of7-fluoro-1H-[1,6]naphthyridin-2-one (8.1 g, 49 mmol) in THF (100 mL) wasprepared, and the alcohol solution was added to this solution viacanula. The reaction was stirred at 80° C. overnight. MS showed mostlyproduct. So reaction quenched with saturated NH₄Cl and water. Thesolution was brought to a pH of 8 and extracted with ethyl acetate. Theorganic layer was washed with brine and concentrated to give a silkysolid. EtOAc was added and the mixture was filtered to give a beigesolid. The NMR indicated that it was the product and it wasrecrystallized from acetonitrile to give clean product. (9.70 g). Thefiltrate was concentrated and filtered to give more precipitate (0.788g). The filtrate was concentrated and purified by chromatography (0-70%EtOAc/hexanes) to give additional product as a beige solid (2.716 g).(Total Product: 13.21 g, 82%). MS: APCl: M+1: 325.2 (Exact Mass:324.15).

A fifth intermediate compound,7-(4-Hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one, wasproduced as follows: To a solution of7-(4-benzyloxy-butoxy)-1H-[1,6]naphthyridin-2-one (7.92 g, 24.4 mmol) inMeOH/THF (100 mL) was added 20% Pd/C (1.5 g) and the mixture washydrogenated for 59 h. The reaction was filtered, concentrated andpurified by liquid chromatography (0-10% MeOH/CH2Cl2) to give the fifthintermediate compound as a white solid (4.11 g, 17.4 mmol, 71%). MS:APCl: M+1: 237.1(Exact Mass: 236.12).

A sixth intermediate compound,4-(2-Oxo-1,2,3,4-tetrahydro-[1,6]naphthyridin-7-yloxy)-butyraldehyde,was produced as follows: To a suspension of7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one (2.0 g, 8.5mmol) in dichloroethane (20 mL) was added IBX (7 g, 25 mmol). This washeated at 80° C. for 5 hours. The reaction was cooled and then filtered.The filter cake was washed with CH₂CH₂ until the product was removed.The filtrate was concentrated to give a yellow solid (1.88 g, used crudein next reaction). MS: APCl: M+1: 235.1 (Exact Mass: 234.10).

A reductive amination procedure similar to Example A1 was followed using1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to give the titlecompound (0.33 g; 56%). MS: APCl: M+1: 435.2 (Exact Mass: 434.27).

Example I3 Synthesis of7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1 was followed using1-naphthalen-1-yl-piperazine to give the title compound (0.480 g, 87%).MS: APCl: M+1: 431.2 (Exact Mass: 430.24).

Example I4 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1 was followed using1-(2,3-dichloro-phenyl)-piperazine to give the title compound (0.48 g;81%). MS: APCl: M+1: 449.1 (Exact Mass: 448.14).

Example I5 Synthesis of7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1 was followed using1-indan-4-yl-piperazine to give the title compound (0.36 g; 66%). MS:APCl: M+1: 421.2 (Exact Mass: 420.25).

Example I6 Synthesis of7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1 was followed using1-(7-fluoro-naphthalen-1-yl)-piperazine to give the title compound (0.31g; 68%). MS: APCl: M+1: 449.3 (Exact Mass: 448.23).

Example I7 Synthesis of8-Bromo-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]naphthyridin-2-one

The first intermediate compound,8-Bromo-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one, wasproduced as follows: To a solution of7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one (1.1 g, 4.7mmol) in DMF (10 mL) was added NBS (0.91 g, 5.1 mmol). The solution wasstirred at room temperature for 2.5 h. The reaction turned a deeperyellow color. H₂O was added and the mixture was extracted with EtOAc.The organic layer was washed with H₂O, and brine, dried over MgSO₄ andconcentrated. Purification by SiO₂chromatography (0-7% MeOH/CH₂Cl₂) gavethe first intermediate compound as an off-white solid (1.16 g, 3.69mmol, 79%). MS: APCl: M+1: 315.0 (Exact Mass: 314.03).

A second intermediate compound,4-(8-Bromo-2-oxo-1,2,3,4-tetrahydro-[1,6]naphthyridin-7-yloxy)-butyraldehyde,was produced as follows: To a suspension of8-bromo-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one (1.1g, 3.5 mmol) in dichloroethane (20 mL) was added IBX (3 g, 10 mmol) .This was heated at 80° C. for 5 hours. The reaction was cooled and thenfiltered. The filter cake was washed with CH₂CH₂ until the product wasremoved. The filtrate was concentrated to give a yellow oil.Purification by SiO₂ chromatography (0-7% MeOH/CH₂Cl₂) gave the secondintermediate compound as a yellow solid (1.01 g). MS: APCl: M+1: 313.1(Exact Mass: 312.01).

A reductive amination procedure similar to Example A1 was followed using1-naphthalen-1-yl-piperazine to give the title compound (0.62 g; 76%).MS: APCl: M+1: 509.4 (Exact Mass: 508.15).

Example I8 Synthesis of8-Bromo-7-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1 was followed using1-(2,3-dichloro-phenyl)-piperazine to give the title compound (0.43 g;51%). MS: APCl: M+1: 527.0 (Exact Mass: 526.05).

Example I9 Synthesis of8-Chloro-7-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A first intermediate compound,8-Chloro-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one,was produced as follows: To a solution of7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one (2.0 g, 8.46mmol) in DMF (23 mL) was added NCS (1.2 g, 9.3 mmol). The solution wasstirred at room temperature for 2 hours and there was no reaction. Thereaction was heated to 80° C. overnight and it went from a colorlesssolution to a dark brown solution. The reaction was cooled and thenwater was added. The mixture was extracted with EtOAc (3×). The organiclayer was washed with H₂O and brine, dried over Na₂SO₄ and concentratedto give a brown oil. Purification by SiO₂ chromatography (0-10%MeOH/CH₂Cl₂) gave the first intermediate compound as a yellow solid(1.10 g, 48%). MS: APCl: M+1: 271.0 (Exact Mass: 270.08).

A second intermediate compound,4-(8-Chloro-2-oxo-1,2,3,4-tetrahydro-[1,6]naphthyridin-7-yloxy)-butyraldehyd,was produced as follows: To a solution of8-chloro-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one(1.05 g, 3.88 mmol) in DCE (25 mL) was added IBX (3.0 g, 12 mmol). Thereaction was heated at 80° C. for 4.5 h. The reaction was cooled andfiltered. The filter cake was washed with CH₂Cl₂ until all productwashed off. The filtrate was concentrated to give a yellow oil, whichsolidified on the pump. Purification by SiO₂ chromatography (0-10%MeOH/CH₂Cl₂) gave a mixture of spots. The second intermediate compoundwas obtained in low yield (0.128 g, 12%). MS: APCl: M+1: 269.0 (ExactMass: 268.06).

A reductive amination procedure similar to Example A1 was followed using1-(2,3-dichloro-phenyl)-piperazine to give the title compound. MS: APCl:M+1: 483.1 (Exact Mass: 482.10).

Example I10 Synthesis of8-Chloro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1 was followed using1-naphthalen-1-yl-piperazine to give the title compound (0.041 g; 38%).MS: APCl: M+1: 465.2 (Exact Mass: 464.20).

Example I11 Synthesis of7-[4-(4-Naphthalen-1-yl)-piperazin-1-yl)-butoxy]-2-oxo-1,2,3,4-tetrahydro-[1,6]naphthyridine-8-carboxylicacid methyl ester

A first intermediate compound,8-Bromo-7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-3,4-dihydro-1H-[1,6]naphthyridin-2-one,was produced as follows: To a solution of8-bromo-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one(1.24 g, 3.93 mmol) in dry CH₂Cl₂ was added dihydropyran (0.49 g, 5.9mmol), followed by pyridinium p-toluenesulfonate (0.099 g, 0.39 mmol).The reaction was stirred at room temperature for 2 days. The reactionmixture was partitioned between ether and brine. The organic layer wasdried over MgSO₄ and concentrated. The residue solidified in therefrigerator to give the first intermediate compound as a white solid(1.57 g). MS: APCl: M+1: 399.1 (Exact Mass: 398.08).

A second intermediate compound,7-(4-Hydroxy-butoxy)-2-oxo-1,2,3,4-tetrahydro-[1,6]naphthyridine-8-carboxylicacid methyl ester, was produced as follows: A 300 mL high pressurereaction vessel was charged with8-bromo-7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-3,4-dihydro-1H-[1,6]naphthyridin-2-one(0.70 g 1.75 mmol), DPPF (0.149 g, 0.175 mmol, 0.1 eq), Et₃N (0.29 mL,2.10 mmol,1.2 eq), and MeOH (100 mL). The vessel was purged and chargedto 400psi with CO. The reaction was heated and stirred at 100° C. for 60hours. The mixture was filtered and concentrated to give a pink solid.Purification by SiO2 chromatography (0-20% MeOH/CH₂Cl₂) gave the secondintermediate compound as a solid (0.381 g, 74%). MS: APCl: M+1: 295.1(Exact Mass: 294.12).

A third intermediate compound,2-Oxo-7-(4-oxo-butoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-8-carboxylicacid methyl ester, was produced as follows: To a suspension of7-(4-hydroxy-butoxy)-2-oxo-1,2,3,4-tetrahydro-[1,6]naphthyridine-8-carboxylicacid methyl ester (0.340 g, 1.15 mmol) in dichloroethane (6 mL) wasadded IBX (1.0 g, 3 mmol). This was heated at 80° C. for 5 hours. Thereaction was cooled and stirred, and then filtered. The filter cake waswashed with CH₂Cl₂ until the product was removed. The filtrate wasconcentrated to give the third intermediate compound as a yellow solid(0.327 g, 97%). MS: APCl: M+1: 293.0 (Exact Mass: 292.11).

A reductive amination procedure similar to Example A1 was followed using1-naphthalen-1-yl-piperazine to give the title compound (0.219 g; 40%).MS: APCl: M+1: 489.1 (Exact Mass: 488.24).

Example I12 Synthesis of8-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A first intermediate compound,7-(4-Hydroxy-butoxy)-8-methyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one,was produced as follows: To a solution of8-bromo-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one (0.1g, 0.3 mmol) in DME (5 mL) was added methylboronic acid (28 mg, 0.48mmol), followed by Pd(PPh₃)₄ (9 mg, 2.5 mol %), and 2M Na₂CO₃. Thereaction was heated at 90° C. for 2 days. The reaction was cooled andextracted with EtOAc (3×), dried over MgSO₄ and concentrated.Purification by SiO₂ chromatography (0-20% MeOH/CH₂Cl₂) gave the firstintermediate compound (0.036 g, 23%). MS: APCl: M+1: 251.1 (Exact Mass:250.13)

A second intermediate compound,4-(8-Methyl-2-oxo-1,2,3,4-tetrahydro-[1,6]naphthyridin-7-yloxy)-butyraldehyde,was produced as follows: To a suspension of7-(4-hydroxy-butoxy)-8-methyl-3,4-dihydro-1H-[1,6]naphthyridin-2-one (60mg, 18.02 mmol) in dichloroethane (6 mL) was added IBX (15 g, 54 mmol).The mixture was heated at 80° C. for 5 hours. The reaction was cooledand stirred, and then filtered. The filter cake was washed with CH₂Cl₂until the product was removed. The filtrate was concentrated to give ared oil. Purification by SiO₂ chromatography (0-7% MeOH/CH₂Cl₂) gave thesecond intermediate compound as a yellow solid (50 mg, 84%). MS: APCl:M+1: 249.1 (Exact Mass: 248.12 ).

A reductive amination procedure similar to Example A1 was followed using1-naphthalen-1-yl-piperazine to give the title compound. MS: APCl: M+1:445.3 (Exact Mass: 444.25).

Example I13 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,6]naphthyridin-2-one

A first intermediate compound,7-(4-Hydroxy-butoxy)-1H-[1,6]naphthyridin-2 -one, was produced asfollows: Butane-1,4-diol (8.24 g, 8.12 mL, 91.3 mmol) was added to solidKOtBu (6 g, 55 mmol). The very viscous mixture was stirred for 15 minbefore adding 7-fluoro-1H-[1,6]naphthyridin-2 -one (3 g, 18 mmol). NMP(60 mL) was then added and the reaction was heated at 70° C. overnight.The reaction was cooled and poured into ice water. No precipitateformed, so the mixture was extracted with EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated. Purification bySiO₂ chromatography (0-50% EtOAc/Hex) gave the first intermediatecompound (2.36 g, 55%). MS: APCl: M+1: 235.0 (Exact Mass: 234.10).

A second intermediate compound,4-(2-Oxo-1,2-dihydro-[1,6]naphthyridin-7-yloxy)-butyraldehyde, wasproduced as follows: To a suspension of7-(4-hydroxy-butoxy)-1H-[1,6]naphthyridin-2-one (2.33 g, 9.95 mmol) indichloroethane (30 mL) was added IBX (8 g, 30 mmol) . The mixture washeated at 80° C. for 5 hours. The reaction was cooled and stirred, andthen filtered. The filter cake was washed with CH₂Cl₂ until the productwas removed. The filtrate was concentrated to give the secondintermediate compound as a yellow solid (2.45 g). MS: APCl: M+1: 233.1(Exact Mass: 232.08).

A reductive amination procedure similar to Example A1 was followed using1-(2,3-dichloro-phenyl)-piperazine to give the title compound. MS: APCl:M+1: 447.1 (Exact Mass: 446.13).

Example I14 Synthesis of7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1 was followed using1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine to give the titlecompound (0.37 g, 66%). MS: APCl: M+1: 433.3 (Exact Mass: 432.25).

Example I15 Synthesis of7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1 was followed using1-indan-4-yl-piperazine to give the title compound (0.206 g, 57%). MS:APCl: M+1: 419.2 (Exact Mass: 418.24).

Example I16 Synthesis of7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1 was followed using1-naphthalen-1-yl-piperazine to give the title compound (0.18 g, 56%).MS: APCl: M+1: 429.2 (Exact Mass: 428.22).

Example I17 Synthesis of7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1 was followed using1-(7-fluoro-naphthalen-1-yl)-piperazine to give the title compound (0.31g, 65%). MS: APCl: M+1: 447.3 (Exact Mass: 446.21).

Example I18 Synthesis of7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butylamino}-1H-[1,6]naphthyridin-2-one

To a mixture of 4-(4-naphthalen-1-yl-piperazin-1-yl)-butylamine (1.00 g,3.31 mmol) and 7-fluoro-1H-[1,6]naphthyridin-2-one (517 mg, 3.15 mmol)in xylenes (6 mL) was added Et₃N (0.7 mL, 4.8 mmol). The mixture washeated at 140° C. for 2 days. The reaction was partitioned betweenCH₂Cl₂ and water. The solubility of the compound in CH₂Cl₂ is poor sosome MeOH was added. The organic layer was washed with saturated NaHCO₃and brine, dried over Na₂SO₄ and concentrated. Purification by liquidchromatography (6-8% MeOH/CH₂Cl₂ with 1% NH₄OH) gave the title compoundas a pale yellow solid (252 mg, 0.565 mmol, 18%). MS: APCl: M+1: 446.1(Exact Mass: 445.14).

Example I19 Synthesis of7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pentyl}-4,4-dimethyl-1,4-dihydro-pyrido[4,3-d][1,3]oxazin-2-one

A first intermediate compound, 4-Amino-6-chloro-nicotinic acid ethylester, was produced as follows: To a solution of 4,6-dichloro-nicotinicacid ethyl ester (15.0 g, 68.2 mmol) in THF was added liquid NH₃. Thebomb was sealed and heated at 65° C. overnight. The reaction wasconcentrated and partitioned between EtOAc and water. The aqueous layerwas extracted with EtOAc. The combined organic layer was washed withsaturated NaHCO₃ and brine, dried over Na₂SO₄ and concentrated to give asolid. Recrystallization from EtOAc/Hexanes gave an off-white solid (1g) which was not product. The filtrate was concentrated, absorbed ontoSiO₂ and purified by liquid chromatography (20-25% EtOAc/Hexanes) togive the first intermediate compound as a white crystalline solid (10.20g, 50.8 mmol, 75%). The structure was confirmed by NMR and massspectrometry. MS: APCl: M+1: 201.0 (Exact Mass: 200.04).

A second intermediate compound,2-(4-Amino-6-chloro-pyridin-3-yl)-propan-2-ol, was produced as follows:A solution of 4-amino-6-chloro-nicotinic acid ethyl ester (2.50 g, 12.5mmol) in Et₂O (20 mL) and THF (10 mL) was added via cannula to asolution of MeMgBr (3M in Et₂O, 20 mL, 60 mmol) in Et₂O (10 mL) cooledto 0° C. The reaction was allowed to warm to room temperature and stirovernight. A thick green precipitate formed on the bottom of the flask.The reaction was quenched by slow addition of water and 1N HCl. Theprecipitate dissolved and the green color disappeared. The mixture wasextracted with Et₂O. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated to give the second intermediate compound as awhite solid (2.13 g, 11.41 mmol, 91%). The structure was confirmed byNMR and mass spectrometry. MS: APCl: M+1: 187.0 (Exact Mass: 186.06).

A third intermediate compound,7-Chloro-4,4-dimethyl-1,4-dihydro-pyrido[4,3-d][1,3]oxazin-2-one, wasproduced as follows: To a solution of2-(4-amino-6-chloro-pyridin-3-yl)-propan-2-ol (500 mg, 2.68 mmol) intoluene (2 mL) and THF (4 mL) was added triethylamine (0.82 mL, 5.90mmol). The reaction was cooled to 0° C. and a 20% solution of phosgenein toluene (1.5 mL, 3.21 mmol) was added. The reaction was allowed towarm to room temperature and stir for 4 h. MeOH was added to quenchexcess phosgene. Dilute aqueous NaHCO₃was added and the mixture wasextracted with EtOAc. The organic layer was washed with saturated NaHCO₃and brine, dried over Na₂SO₄ and concentrated. Purification by liquidchromatography (30-35% EtOAc/Hexanes) afforded the third intermediatecompound as a white solid (0.43 g, 2.02 mmol, 75%). The structure wasconfirmed by NMR and mass spectrometry. MS: APCl: M+1: 213.0 (ExactMass: 212.04).

A fourth intermediate compound,7-(5-Chloro-pent-1-enyl)-4,4-dimethyl-1,4-dihydro-pyrido[4,3-d][1,3]oxazin-2-one,was produced as follows: To a solution of7-chloro-4,4-dimethyl-1,4-dihydro-pyrido[4,3-d][1,3]oxazin-2-one (444mg, 2.09 mmol) in dimethoxyethane (10 mL)was added Pd(Ph₃P)₄ (72 mg,0.063 mmol, 3 mol %). 5-Chloro-1-pentenyl boronic acid (700 mg, 4.72mmol) was added as a slurry in DME (2 mL) via a pipet, followed by 2MNa₂CO₃ (465 mg in 2.2 mL H₂O, 4.39 mmol). The reaction was refluxedovernight. The reaction was concentrated and THF was added. The mixturewas sonicated for 2 min and the resulting suspension was filteredthrough Celite. The filtrate was concentrated and purified by liquidchromatography (50-60% EtOAc/Hexanes) to give the fourth intermediatecompound as a white solid (440 mg, 1.57 mmol, 75%). The structure wasconfirrned by NMR and mass spectrometry. MS: APCl: M+1: 281.0 (ExactMass: 280.10).

A fifth intermediate compound,7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4,4-dimethyl-1,4-dihydro-pyrido[4,3-d][1,3]oxazin-2-one, was produced as follows: To a mixture of7-(5-chloro-pent-1-enyl)-4,4-dimethyl-1,4-dihydro-pyrido[4,3-d][1,3]oxazin-2-one(435 mg, 1.55 mmol) in CH₃CN was added a solution of1-(2,3-dichloro-phenyl)-piperazine (620 mg, 2.68 mmol) in CH₃CN (5 mL)via cannula. K₂CO₃ (428 mg, 3.1 mmol) and KI (52 mg, 0.31 mmol) wereadded and the reaction was refluxed for 40 h. The mixture was filteredand washed with CH₃CN. The filtrate was concentrated and partitionedbetween EtOAc and water. The organic layer was washed with saturatedNaHCO₃ and brine, dried over Na₂SO₄ and concentrated. Purification byliquid chromatography (5% MeOH/CH₂Cl₂ with 0.5% NH₄OH) afforded thefourth intermediate compound as a pinkish-white foam (558 mg, 1.17 mmol,76%). MS: APCl: M+1: 475.1 (Exact Mass: 474.16).

7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4,4-dimethyl-1,4-dihydro-pyrido[4,3-d][1,3]oxazin-2-one(452 mg, 0.95 mmol) was hydrogentated using Ra—Ni in EtOH/THF. Thereaction was filtered and concentrated. Purification by liquidchromatography (5% MeOH/CH₂Cl₂ with 0.5% NH₄OH) gave a white foam (385mg, 85% pure). The foam was dissolved in a minimal amount of EtOAc and,upon standing, a white precipitate formed. The precipitate was filteredand washed with Et₂O to give the title compound as a white solid (200mg, 0.42 mmol, 44%). MS: APCl: M+1: 477.1 (Exact Mass: 476.17).

EXAMPLES SET 3 Example A1′ Synthesis of7-{4-[4-(2-Oxo-2,3-dihydro-benzooxazol-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, 2-Benzyloxy-7-chloro-[1,8]naphthyridine,was produced as follows: To a solution of benzyl alcohol (5.0 mL, 48.0mmol) in THF (50 mL) cooled to 0° C. was added KO^(t)Bu (1M in THF, 46mL, 46.0 mmol). The solution was stirred at 0° C. for 20 min and thenadded via cannula to a suspension of 2,7-dichloro-[1,8]naphthyridine(10.0 g, 50.2 mmol, J. Org. Chem. 1981, 46, 833) in DMF (50 mL) and THF(50 mL) cooled to 0° C. The orange suspension was stirred at 0° C. for15 min and at room temperature for 30 min. The reaction was quenchedwith saturated NH₄Cl and H₂O. The mixture was extracted with EtOAc. Theorganic layer was filtered through celite to remove an orange clay-likeprecipitate. The organic layer was washed with H₂O and brine, andconcentrated to give an orange solid. The solid was absorbed onto SiO₂and purified by liquid chromatography (2% EtOAc/48% Hexanes/50% CH₂Cl₂)to give the first intermediate compound as a white solid (6.37 g, 23.5mmol, 51%). MS: APCl: M+1: 271.0 (Exact Mass: 270.06).

A second intermediate compound,2-Benzyloxy-7-(4-benzyloxy-butoxy)-[1,8]naphthyridine, was produced asfollows: To a solution of 4-benzyloxy-1-butanol (4.9 mL, 28.2 mmol, 1.2equiv) in THF (20 mL) cooled to 0° C. was added KO^(t)BU (1M in THF, 27mL, 27 mmol, 1.15equiv). The solution was stirred at 0° C. for 20 minand then added via cannula to a suspension of2-benzyloxy-7-chloro-[1,8]naphthyridine (6.35 g, 23.5 mmol) in THF (70mL) cooled to 0° C. The reaction became homogenous. After 30 min at 0°C., saturated NH₄Cl and H₂O were added to quench the reaction. Themixture was extracted with EtOAc. The organic layer was washed withsaturated NaHCO₃, H₂O and brine, dried over Na₂SO₄ and concentrated. Thecrude was absorbed onto SiO2 and purified by liquid chromatography(10-15% EtOAc/Hexanes) to give the second intermediate compound as ayellow oil (4.64 g, 11.19 mmol, 48%). MS: APCl: M+1: 415.2 (Exact Mass:414.19).

A third intermediate compound,7-(4-Hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one, wasproduced as follows: To a solution of2-benzyloxy-7-(4-benzyloxy-butoxy)-[1,8]naphthyridine (4.64 g, 11.19mmol) in MeOH (100 mL) was added 20% Pd/C (1.5 g) and the mixture washydrogenated for 22 h. The reaction was filtered, concentrated andpurified by liquid chromatography (5% MeOH/CH2Cl2) to give the thirdintermediate compound as a white solid (2.44 g, 10.33 mmol, 92 %). MS:APCl: M+1: 237.1 (Exact Mass: 236.12).

7-(4-Hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one was alsoprepared by hydrogenation of7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one (intermediate in ExampleB1).

A fourth intermediate compound,4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde wasproduced by oxidizing the third intermediate compound using either aDess-Martin oxidation reaction or a Swern oxidation reaction, asfollows:

Dess-Martin oxidation: To a cloudy solution of Dess-Martin periodinane(2.80 g, 6.60 mmol, 1.5 equiv) in CH₂Cl₂ (13 mL) was added a solution of7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one (1.04 g,4.40 mmol) in CH₂Cl₂ (25 mL) via cannula. The reaction was stirred atroom temperature for 5 h and stored in the freezer overnight. A 1:1mixture of saturated Na₂S₂O₃ and saturated NaHCO₃ (50 mL) was addedfollowed by Et₂O. The mixture was stirred for 10 min and then extractedwith Et₂O/EtOAc (2:1). The organic layer was washed with saturatedNaHCO₃ and brine, dried over Na₂SO₄ and concentrated to give the fourthintermediate compound as a pale yellow oil (1.06 g, used crude in nextreaction). MS: APCl: M+1: 235.1 (Exact Mass: 234.10).

Swern oxidation: A solution of oxalyl chloride (9.97 mL, 112 mmol) inCH₂Cl₂ was cooled to −70° C. and DMSO (15.6 mL, 220 mmol) was carefullyadded. The solution was stirred at −60° C. for 10 min and then asolution of 7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one(23 g, 97.5 mmol) in DMSO (70 mL) was added dropwise at −50˜−60° C. Thereaction mixture was stirred at −60° C. for 20 min and thentriethylamine (72 mL, 0.513 mol) was added dropwise. The reaction waswarmed to room temp and stirred for 30 min. The mixture was poured intoice-water and the organic phase was separated. The aqueous phase wasextracted with CH₂Cl₂, combined with the organic phase, washed withbrine, dried over Na₂SO₄, and concentrated under vacuum to give thecrude product. Purification by column chromatography (hexane: ethylacetate 2:1) followed by recrystallization provided the fourthintermediate compound (12.7 g, 54.3 mmol, 56%).

To a solution of4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(300 mg, 1.28 mmol) in DCE (6 mL) was added7-piperazin-1-yl-3H-benzooxazol-2-one (309 mg, 1.41 mmol, preparedaccording to EP 0189612 and/or EP 0138280; Drugs of the Future, 2001,26, 128). The piperazine did not dissolve so DMF (1 mL) was added. Thereaction was stirred for 10 min and NaBH(OAc)3 (380 mg, 1.79 mmol) wasadded. The reaction was stirred for 2 h at RT. Saturated NaHCO3was addedand the mixture was extracted with EtOAc (along with a little MeOH). Theorganic layer was washed with H2O and brine, and concentrated to give alight brown solid. The solid was dissolved in CH2Cl2/MeOH, absorbed ontoSiO2 and purified by liquid chromatography (AnaLogix, RS-40, 0-5%MeOH/CH2Cl2) to give a white solid. Et2O was added and the solid wascollected by filtration and dried to give the product as a white solid(360 mg, 0.823 mmol, 64%). MS: APCl: M+1: 438.2 (Exact Mass: 437.21).

A variation of this same method was used to produce other compounds asdescribed in examples below, wherein other compounds were substitutedfor 7-piperazin-1-yl-3H-benzooxazol-2-one in the final step of thesynthesis procedure.

Example A2′ Synthesis of7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound4-(2,3-Dihydro-benzofuran-7-yl)-piperazine-1-carboxylic acid tert-butylester, was produced as follows: A solution ofbis-(dibenzylideneacetone)palladium(0) (4.92 g, 0.16 mol) and toluene(2500 ml) was degassed with nitrogen for 15 minutes. (Note: Degassingwas continued during each addition. Time between additions was 15minutes.) Then added was tri-o-tolylphosphine (4.92 g, 0.16 mol) thensodium t-butoxide (53.8 g, 0.56 mol) then Boc-piperazine (86.8 g, 0.47mol) then a solution of 7-bromo-2,3-dihydro-benzofuran (79.6 g, 0.40mol, prepared according to Tetrahedron Lett. 1998, 39, 2219) in toluene(100 ml). The reaction mixture was stirred at reflux for 16 h. By TLC,all starting material had been consumed. The cooled reaction mixture wasfiltered over a pad of Celite. The filtrate was concentrated underreduced pressure and the residue was triturated with ethyl acetate inheptane (50%). The insoluble material was filtered off and that filtratewas concentrated under reduced pressure. The crude residue was purifiedby flash column chromatography using ethyl acetate in heptane (50%) togive 46.4 g (38% yield) of the first intermediate compound as a tansolid.

A second intermediate compound,1-(2,3-Dihydro-benzofuran-7-yl)-piperazine dihydrochloride, was producedas follows: A solution of4-(2,3-dihydro-benzofuran-7-yl)-piperazine-1-carboxylic acid tert-butylester (42.3 g, 0.139 mol) in ethyl acetate (420 ml) was cooled in an icebath to 0° C. HCl in ethyl acetate (3M, 1.05 mol, 350 ml) was addeddropwise. The reaction mixture was stirred at 0° C. for 1 h, at ambienttemperature for 6 h, at 50° C. for 2 h, at ambient temperature for 16 h,and at 50° C. for 2 h. The resulting suspension was cooled and theresulting solid was collected and washed with ethyl acetate then driedin a vacuum oven at 70° C. to give 32.76 g (79% yield as the di-HClsalt) of the second intermediate compound as a tan solid. Mp:decomposition at 200° C.

A reductive amination procedure similar to Example A1′ was followedusing 1-(2,3-dihydro-benzofuran-7-yl)-piperazine dihydrochloride to givethe title compound. MS: APCl: M+1: 423.2 (Exact Mass: 422.23).

Example A3′ Synthesis of7-{4-[4-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound2,2-Dimethyl-2,3-dihydro-benzofuran-7-ylamine, was produced as follows:To a mixture of 2,2-dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid(Maybridge, 6.15 g, 32.0mmo) in dry tert-butanol (100 mL) was added Et₃N(8.9 mL, 64.0 mmol) and the mixture became homogenous. DPPA (8.3 mL,38.4 mmol) was added and the reaction was refluxed overnight. Thereaction was concentrated and diluted with EtOAc. The organics werewashed with water (2×) and brine, dried over Na₂SO₄ and concentrated.Purification by SiO₂ chromatography (AnaLogix RS-120, 2-25% EtOAc/Hex)gave (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-carbamic acid tert-butylester as a clear oil (6.33 g, 24.0 mmol, 75%).

To a solution of (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-carbamicacid tert-butyl ester (6.33 g, 24.0 mmol) in CH₂Cl₂ (30 mL) was addedTFA (25 mL). The reaction bubbled for about 5 minutes and was stirred atroom temperature for 1 h. The reaction was concentrated. The crudematerial was partitioned between EtOAc and aqueous NaHCO₃. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated to givethe first intermediate compound as a light brown liquid (3.83 g, 23.5mmol, 97%). MS: APCl: M+1: 164.1 (Exact Mass: 163.10).

A second intermediate compound,1-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazine, was produced asfollows: A mixture of 2,2-dimethyl-2,3-dihydro-benzofuran-7-ylamine(3.83 g, 23.5 mmol), bis-(2-chloroethyl)amine hydrochloride (4.61 g,25.8 mmol), Nal (1.76 g, 11.7 mmol) and hexyl alcohol (3 mL) inchlorobenzene (60 mL) was heated at 140° C. overnight. The mixture wasconcentrated and the residue was stirred 2× with 50% Et₂O/Hexanes. Thesolvent was decanted and a light brown solid remained in the flask. Theresidue was dissolved in MeOH/CH₂Cl₂ and absorbed onto SiO₂.Purification by SiO₂ chromatography (8% MeOH/CH₂Cl₂ with 1% NH₄OH) gavethe second intermediate compound as a light brown oil which partiallysolidified on the pump (5.05 g, 21.7 mmol, 93%). The gooey solid wastriturated with ether to give an off-white solid which was filtered,washed with ether and dried. MS: APCl: M+1: 233.2 (Exact Mass: 232.16).

A reductive amination procedure similar to Example A1′ was followedusing 1-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazine to givethe title compound. MS: APCl: M+1: 451.2 (Exact Mass: 450.26).

Example A4′ Synthesis of7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-3.4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound 4-Chroman-8-yl-piperazine-1-carboxylicacid tert-butyl ester, was produced as follows: The reaction was done intwo batches on the following scale: A suspension of Pd₂ (dba)₃ (0.48 g,0.53 mmol) in toluene (500 mL) was purged/degassed with N₂ (directlyinto the solution). To this was charged rac-BINAP (0.99 g, 1.6 mmol),sodium t-butoxide (28.4 g, 0.30 mol), Boc-piperazine (46 g, 0.247 mol)and lastly 8-bromo-chroman (45 g, 0.21 mol, prepared according toTetrahedron Lett. 1998, 39, 2219) after which time the purge line wasremoved and the reaction continued under an atmosphere of N₂. Thereaction was heated to 80-85° C. over 16 h (monitor by TLC, 9:1heptane:EtOAc, UV, I₂). After cooling the two batches were filteredthrough Celite, combined and the solvent evaporated. Chromatography (3:1heptane: EtOAc) and trituration of the resulting solid gave 98.6 g (74%)of the first intermediate compound in two crops.

A second intermediate compound, 1-Chroman-8-yl-piperazinedihydrochloride, was produced as follows: A solution of4-chroman-8-yl-piperazine-1-carboxylic acid tert-butyl ester (75.0 g,0.236 mol) and ethyl acetate (590 ml) was cooled in an ice bath to 0° C.HCl in ethyl acetate (3M; 1.77 mol; 590 ml) was added dropwise. Thereaction mixture was stirred at 0° C. for 1 h, at ambient temperaturefor 20 h and at 50° C. for 6 h (monitor by LCMS). The resultingsuspension was cooled and the solid was collected, washed with ethylacetate then dried in a vacuum oven at 70° C. to give 67.41 g (94% yieldas the di-HCl salt) of the second intermediate compound as a whitesolid.

A reductive amination procedure similar to Example A1′ was followedusing 1-chroman-8-yl-piperazine dihydrochloride to give the titlecompound. MS: APCl: M+1: 437.2 (Exact Mass: 436.25).

Example A5′ Synthesis of7-{4-[4-(2,2-Dimethyl-2H-chromen-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound1-Bromo-2-(1,1-dimethyl-prop-2-ynyloxy)-benzene, was produced asfollows: To a solution of 2-methyl-3-butyn-2-ol (4.47 g, 53.2 mmol) inCH₃CN (30 mL) cooled to 0° C. was added DBU (10.4 mL, 1.5 eq), followedby dropwise addition of trifluoroacetic acid anhydride (7.5 mL, 53.2mmol) over 20 min. The resultant yellow solution was stirred at 0° C.for 40 min. In a separate flask, a solution of 2-bromophenol (8.00 g,46.2 mmol) in CH₃CN (30 mL) cooled to 0° C. was treated with DBU (9.0mL, 1.3 eq), followed by CuCl₂ (17 mg). To this green solution was addedthe above 2-methyl-3-butyn-2-ol trifluoroacetate solution via cannulaover 20 min at 0° C. The reaction was stirred to 2 h at 0° C. and thenstored in the refrigerator overnight. The reaction was concentrated andthen partitioned between hexanes and water. The aqueous layer wasextracted with hexanes. The combined organic layer was washed with 1NHCl, 1N NaOH (2×) and brine, dried over MgSO₄ and concentrated to givethe first intermediate compound as a clear oil (8.25 g, 34.5 mmol, 75%).Crude NMR looked clean.

A second intermediate compound, 8-Bromo-2,2-dimethyl-2H-chromene, wasproduced as follows: To 20 mL of N,N-diethylaniline at 180° C. was added1-bromo-2-(1,1-dimethyl-prop-2-ynyloxy)-benzene (8.0 g, 33.5 mmol) viasyringe under nitrogen. The solution was heated at 190° C. overnight (22h). The reaction is difficult to follow by TLC. The reaction was allowedto cool and then poured into a mixture of hexanes and 1N HCl. Theorganic layer was washed with 1N HCl (2×) and brine, dried over MgSO₄and concentrated to give the second intermediate compound as a yellowliquid (7.40 g, 30.9 mmol, 92%). Crude NMR looks good.

A third intermediate compound,4-(2,2-Dimethyl-2H-chromen-8-yl)-piperazine-1-carboxylic acid tert-butylester, was produced as follows: A solution of8-bromo-2,2-dimethyl-2H-chromene (7.22 g, 30.2 mmol) in dry toluene (60mL) was degassed for 10 min by blowing nitrogen into the solution. Thissolution was then added via cannula to a flask containing Pd₂ (dba)₃(360 mg, 0.393 mmol, 2.5 mol % in Pd), di-tert-butylphosphino biphenyl(451 mg, 1.51 mmol, 5 mol %), NaOtBu (4.06 g, 42.3 mmol) andBoc-piperazine (6.75 g, 36.2 mmol) under nitrogen. The reaction mixturewas heated at 80° C. overnight (17 h). MS showed a large product peak.The reaction was allowed to cool to room temperature and Et₂O was added.The mixture was filtered through Celite washing with Et₂O. The filtratewas washed with 0.5 M citric acid (3×, to remove excess Boc-piperazine)and once with brine, dried over Na₂SO₄ and concentrated to give a darkred oil (approx. 10 g). Purification by SiO₂ chromatography (10%EtOAc/Hexanes) gave the third intermediate compound as a yellow oilwhich partially solidified under vacuum (4.94 g, 14.3 mmol, 48%). MS:APCl: M+1: 345.2 (Exact Mass: 344.21).

A fourth intermediate compound,1-(2,2-Dimethyl-2H-chromen-8-yl)-piperazine, was produced as follows: Toa solution of 4-(2,2-dimethyl-2H-chromen-8-yl)-piperazine-1-carboxylicacid tert-butyl ester (2.43 g, 7.05 mmol) in CH2Cl2 (15 mL) was addedTFA (12 mL). The reaction turned brown and was stirred at roomtemperature for 2 h. The reaction was concentrated 2× from CH2Cl2. Theresidue was taken up in 5% MeOH/CH2Cl2 with 1% NH4OH and the mixturesmoked. The solution was concentrated to give a brown oil. Purificationby SiO2 chromatography (8% MeOH/CH2Cl2 with 1% NH4OH) gave the fourthintermediate compound as pale brown oil which solidified to give a tansolid (1.19 g, 4.87 mmol, 69%).

A reductive amination procedure similar to Example A1′ was followedusing 1-(2,2-dimethyl-2H-chromen-8-yl)-piperazine to give the titlecompound. MS: APCl: M+1: 463.2 (Exact Mass: 462.26).

Example A6′ Synthesis of7-{4-[4-(2,2-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound4-(2,2-Dimethyl-chroman-8-yl)-piperazine-1-carboxylic acid tert-butylester, was produced as follows:4-(2,2-Dimethyl-2H-chromen-8-yl)-piperazine-1-carboxylic acid tert-butylester (2.50 g, 7.26 mmol) was hydrogenated in the HPL using 10% Pd/C(1.0 g) in MeOH (50 mL) for 1.5 h. The reaction was filtered andconcentrated to give a yellow oil. The crude oil was absorbed onto SiO₂and purified by chromatography (10% EtOAC/Hexanes) to give the firstintermediate compound as a clear oil which solidified to give a whitesolid (1.92 g, 5.54 mmol, 76%). MS: APCl: M+1: 347.1 (Exact Mass:346.23).

A second intermediate compound,1-(2,2-Dimethyl-chroman-8-yl)-piperazine, was produced as follows: To asolution of 4-(2,2-dimethyl-chroman-8-yl)-piperazine-1-carboxylic acidtert-butyl ester (1.90 g, 5.48 mmol) in CH₂Cl₂ (10 mL) cooled to 0° C.was added TFA (10 mL). The ice bath was removed and the solution wasstirred at room temperature for 1 h. The reaction was concentrated 2×from CH₂Cl₂ to give a light brown oil which solidified on the pump togive the second intermediate compound as a white solid as the tris-TFAsalt (3.12 g, 5.30 mmol, 97%). MS: APCl: M+1: 247.2 (Exact Mass:246.17).

A reductive amination procedure similar to Example A1′ was followedusing 1-(2,2-dimethyl-chroman-8-yl)-piperazine to give the titlecompound. MS: APCl: M+1: 465.2 (Exact Mass: 464.28).

Example A7′ Synthesis of7-{4-[4-(Spiro[chromene-2,1′-cyclopentan]-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound,1-Spiro[chromene-2,1′-cyclopentan]-8-ylpiperazine was produced asfollows: The procedures in Example A5′ were followed starting from1-ethynyl-cyclopentanol to give the intermediate compound. MS: APCl:M+1: 271.0 (Exact Mass: 270.17).

A reductive amination procedure similar to Example A1′ was followedusing 1-spiro[chromene-2,1′ -cyclopentan]-8-ylpiperazine to give thetitle compound. MS: APCl: M+1: 489.3 (Exact Mass: 488.28).

Example A8′ Synthesis of 7-{4-[4-(3,4-Dihydrospiro[chromene-2,1′-cyclopentan]-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound1-(3,4-Dihydrospiro[chromene-2,1′-cyclopentan]-8-yl)piperazine, wasproduced as follows: The procedure in Example A6′ was followed to givethe intermediate compound. MS: APCl: M+1: 273.1 (Exact Mass: 272.19).

A reductive amination procedure similar to Example A1′ was followedusing 1-(3,4-dihydrospiro[chromene-2,1′-cyclopentan]-8-yl)piperazine togive the title compound. MS: APCl: M+1: 491.3 (Exact Mass: 490.29).

Example A9′ Synthesis of7-{4-[4-(2-Methyl-2H-chromen-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound 1-(2-Methyl-2H-chromen-8-yl)-piperazine, wasproduced as follows: The procedures in Example A5′ were followedstarting from but-3-yn-2-ol to give the intermediate compound. MS: APCl:M+1: 231.1 (Exact Mass: 230.14).

A reductive amination procedure similar to Example A1′ was followedusing 1-(2-methyl-2H-chromen-8-yl)-piperazine to give the titlecompound. MS: APCl: M+1: 449.3 (Exact Mass: 448.25).

Example A10′ Synthesis of7-{4-[4-(2-Methyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound, 1-(2-Methyl-chroman-8-yl)-piperazine, wasproduced as follows: The procedure in Example A6′ was followed to givethe intermediate compound. MS: APCl: M+1: 233.1 (Exact Mass: 232.16).

A reductive amination procedure similar to Example A1′ was followedusing 1-(2-methyl-chroman-8-yl)-piperazine to give the title compound.MS: APCl: M+1: 451.3 (Exact Mass: 450.26).

Example A11′ Synthesis of 7-{4-[4-(2,3-Dihydro-benzofuran-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound, 1-(2,3-Dihydro-benzofuran-4-yl)-piperazine,was produced as follows: A 1 L, 3-necked flask equipped with amechanical stirrer, thermometer and a nitrogen inlet was charged with asolution of 2,3-dihydro-benzofuran-4-ylamine (12.5 g, 0.092 mol, J.Heterocyclic Chem. 1980, 17, 1333) in chlorobenzene (220 mL) and1-hexanol (10 mL). The mixture was treated with diisopropylethylamine(8.2 g, 0.063 mol), stirred for 10 min, and then Nal was added (4.4 g,0.029 mol), followed by bis-(2-chloroethyl)amine hydrochloride (16.9 g,0.094 mol). The mixture was refluxed for 16 h at an external temperatureof 140° C. The reaction mixture was cooled to room temperature,evaporated under vacuum and the dark thick liquid was dissolved inchloroform-methanol (9:1) containing a few drops of ammonia, absorbedonto silica gel and purified by silica gel chromatography, using 5%methanol in chloroform for elution. The product was obtained as a thickpaste after evaporation of the main fractions, which upon triturationwith CH₂Cl₂ gave the intermediate compound as white powder (8.0 g, 38%).

A reductive amination procedure similar to Example A1′ was followedusing 1-(2,3-dihydro-benzofuran-4-yl)-piperazine to give the titlecompound. MS: APCl: M+1: (Exact Mass: 422.23).

Example A12′ Synthesis of7-{4-[4-(1,3-Dihydro-isobenzofuran-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound 1,2-Bis-bromomethyl-3-nitro-benzene, wasproduced as follows: To a dry flask under an inert atmosphere containing1,2-dimethyl-3-nitro-benzene (17.00 g, 112.4 mmol, 1eq) in 70 mL of CCl₄was added NBS (43.06 g, 241.9 mmol, 2.1 eq) and benzoyl peroxide (0.274g, 1.131 mmol, 0.01 eq). The orange colored suspension was refluxed fortwo hours before an additional 1.074 g benzoyl peroxide was added. Thereaction was refluxed for two hours and then cooled to room temperature.The reaction mixture was filtered and washed with CCl₄to remove a whitesolid. The yellow filtrate was concentrated to give the firstintermediate compound as a crude oil (30.954 g, 89%).

A second intermediate compound, 4-Nitro-1,3-dihydro-isobenzofuran, wasproduced as follows: To a flask containing1,2-bis-bromomethyl-3-nitro-benzene (1.129 g, 3.655 mmol, 1 eq) wasadded alumina (15 g, 147 mmol, 40 eq) and toluene (10 mL) and themixture was heated at 120° C. for two hours. The reaction mixture wasfiltered to remove the alumina and washed with ethyl acetate. Thefiltrate was concentrated to give a yellow solid which was purified bychromatography on silica gel (0-10% EtOAc: hexane) to afford the secondintermediate compound (0.546 g, 90%). MS: APCl: M−1: 164.9 (Exact Mass:165.04).

A third intermediate compound, 1,3-Dihydro-isobenzofuran-4-ylamine, wasproduced as follows: A solution of 4-nitro-1,3-dihydro-isobenzoturan(5.976 g, 36.19 mmol) in 100 mL of THF was hydrogenated using Ra/Ni. Thereaction was filtered and then concentrated to obtain the thirdintermediate compound (4.996 g, 100%). MS: APCl: M+1: 136.2 (Exact Mass:135.07).

A fourth intermediate compound,1-(1,3-Dihydro-isobenzofuran-4-yl)-piperazine, was produced as follows:To a reaction flask containing a solution of1,3-dihydro-isobenzofuran-4-ylamine (0.488 g, 3.610 mmol, 1 eq) inchlorobenzene (6 mL), was added bis-(2-chloro-ethyl)-amine hydrochloride(0.907 g, 4.260 mmol, 1.18 eq) and diisopropylethyl amine (0.297 g, 2.30mmol, 0.64 eq). The reaction was refluxed for 14 hours. The reaction wascooled and concentrated. Purification by chromatography on silica gel(0-40% MeOH/NH4OH: CH2Cl2) afforded the fourth intermediate compound(0.400 g, 54%). MS: APCl: M+1: 205.1 (Exact Mass: 204.13).

To a suspension of4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde(0.278 g, 1.186 mmol, 1.1 eq) and1-(1,3-dihydro-isobenzofuran4-yl)-piperazine (0.217 g, 1.064 mmol, 1 eq)in dichloroethane (5 mL) was added NaBH(OAc)₃ (0.469 g, 4.425 mmol, 3.73eq). The slurry was allowed to stir overnight at room temperature (18h). The mixture was diluted with EtOAc and quenched with saturatedNaHCO₃. The organic phase was then washed with brine, dried over Na₂SO₄,filtered and evaporated in vacuo. Purification by silica gelchromatography (2% MeOH/CH₂Cl₂) followed by formation of the HCl saltusing 1N HCl in ether provided the title compound (0.143 g, 26%). CHNFound: C, 64.37; H, 6.54; N, 12.13. This calculates out forC24H30N4O3×1.00 HCl.

Example A13′ Synthesis of7-[4-(4-Chroman-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound 3-Nitro-2-vinyl-phenol, was produced asfollows: To a degassed solution of 2-bromo-3-nitro-phenol (3.00 g, 13.8mmol) and tributylvinyltin (4.4 mL, 15.1 mmol) in toluene (70 mL) wasadded tetrakis(triphenylphosphine)palladium(0) (1.59 g, 1.38 mmol, 10mol %). The reaction was refluxed overnight. The mixture was filteredthrough celite washing with EtOAc. The solvent was removed and theresidue was purified by SiO₂ chromatography (AnaLogix RS-120, 10-30%EtOAc/Hexanes) to give the first intermediate compound as a yellowishorange solid (1.00 g, 6.06 mmol, 44%). MS: APCl: M−1: 163.9 (Exact Mass:165.04).

A second intermediate compound, 1-Allyloxy-3-nitro-2-vinyl-benzene, wasproduced as follows: To a solution of 3-nitro-2-vinyl-phenol (1.0 g, 6.1mmol) in acetone (20 mL). was added allyl bromide (1.05 mL, 12. 1 mmol,2 eq) followed by K₂CO₃ (1.67 g, 12.1 mmol, 2 eq). The mixture wasrefluxed for 30 min and stirred at room temperature overnight. Thereaction mixture was filtered washing with acetone and thenconcentrated. Purification by SiO₂ chromatography (AnaLogix RS-40, 2-5%EtOAc /Hexanes) gave the second intermediate compound as an orange oil(1.00 g, 4.87 mmol, 80%).

A third intermediate compound, 5-Nitro-2H-chromene, was produced asfollows: To a solution of 1-allyloxy-3-nitro-2-vinyl-benzene (1.0 g, 4.9mmol) in CH₂Cl₂ (25 mL) was added the 2 nd generation Grubbs catalyst(207 mg, 5 mol %). The reaction was stirred at room temperature for 3 h.The mixture was concentrated and purified by SiO₂ chromatography(AnaLogix RS-40, 2-5% EtOAc/Hexanes) to give the third intermediatecompound as a yellow solid (852 mg, 4.81 mmol, 98%). MS: APCl: M−1:175.9 (Exact Mass: 177.04).

A fourth intermediate compound, Chroman-5-ylamine, was produced asfollows: 5-Nitro-2H-chromene (800 mg, 4.52 mmol) was hydrogenated using10% Pd/C in MeOH (50 mL) for 4.6 h. The yellow solution turned clear.The reaction mixture was concentrated to give the fourth intermediatecompound as a light brown oil which looked pure by NMR and TLC (679 mg,quant). MS: APCl: M+1: 150.3 (Exact Mass: 149.08).

A fifth intermediate compound, 1-Chroman-5-yl-piperazine, was producedas follows: To a solution of chroman-5-ylamine (679 mg, 4.55 mmol) inchlorobenzene (12 mL) and hexanol (0.6 mL) was addedbis(2-chloroethyl)amine hydrochloride (894 mg, 5.01 mmol), Nal (341 mg,2.28 mmol) and diisopropylethylamine (0.44 mL, 2.50 mmol). The reactionwas refluxed at 140° C. for 20 h. A tan ppt formed. The reaction wasallowed to cool to room temperature and hexanes was added. The mixturewas filtered and washed with hexanes. The solid was dissolved inMeOH/CH₂Cl₂ and absorbed ontio SiO₂. Purification by SiO₂ chromatography(8-10% MeOH/CH₂Cl₂ with 1% NH₄OH) gave the fifth intermediate compoundas a light tan solid (548 mg, 2.51 mmol, 55%). MS: APCl: M+1: 219.1(Exact Mass: 218.14).

A reductive amination procedure similar to Example A1′ was followedusing 1-chroman-5-yl-piperazine to give the title compound. MS: APCl:M+1: 437.3 (Exact Mass: 436.25).

Example A14′ Synthesis of7-[4-(4-lsochroman-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound1-Bromo-2-[2-(2-methoxy-ethoxymethoxy)-ethyl]-benzene, was produced asfollows: To a solution of 2-(2-bromo-phenyl)-ethanol (7.8 g, 38.8 mmol)and diisopropylethylamine (8.02 g, 62 mmol) in 50 mL of dry CH₂Cl₂ wasadded MEM chloride (6.26 g, 50.4 mmol) dropwise at 0° C. The resultingmixture was stirred at the same temperature for 2 h and treated with 1NHCl and CH₂Cl₂ . The organic layer was washed with H₂O, dried overNa₂SO₄, concentrated under vacuum. The residue was purified bychromatography (25% EtOAc/hexanes) to give the first intermediatecompound (9.0 g, 80%). ¹H NMR (400 MHz, CDCl₃) δ 7.53 (dd, J=1.5 Hz,J=7.8 Hz, 1 H), 7.29-7.23 (m, 2 H), 7.09-7.05 (m, 1 H), 4.71 (s, 2 H),3.80 (t, J=7.8 Hz, 2 H), 3.62-3.60 (m, 2 H), 3.51-3.49 (m, 2 H), 3.37(s, 3 H), 3.04 (t, J=7.8 Hz, 4 H).

A second intermediate compound, 5-Bromo-isochroman, was produced asfollows: To a solution of1-bromo-2-[2-(2-methoxy-ethoxymethoxy)-ethyl]-benzene (4.5 g, 15.56mmol) in 100 mL of CH₂Cl₂ was added a solution of TiCl₄ in CH₂Cl₂dropwise at 0° C. The resulting mixture was stirred at the sametemperature for 1 h and treated with H₂O and CH₂Cl₂ . The organic layerwas washed with H₂O, dried over Na₂SO₄, and concentrated under vacuum.The residue was purified by chromatography (25% EtOAc/hexanes) to givethe second intermediate compound (2.7 g, 82%). ¹H NMR (400 MHz, CDCl₃)67 7.43 (d, J=7.8 Hz, 1 H), 7.05 (t, J=7.8 Hz, 1 H), 6.95 (d, J=7.3 Hz,1 H), 4.73 (s, 2 H), 4.00 (t, J=5.9 Hz, 2 H), 3.82 (t, J=5.9 Hz, 2 H).

A third intermediate compound, 1-lsochroman-5-yl-piperazine, wasproduced as follows: To a mixture of 5-bromo-isochroman (1 g, 4.69mmol), 1-boc-piperazine (1.05 g, 5.6 mmol), 2-dicyclohexylphosphinobiphenyl (0.066 g, 0.19 mmol), and Pd(OAc)₂ (0.42 g, 0.19 mmol) in 10 mLof dry degassed C₆H₅CH₃was added NaOtBu (0.63 g, 6.6 mmol) at roomtemperature. The resulting mixture was stirred at 80-90° C. for 1 h,cooled and passed through a pad of celite and the filtrate wasconcentrated under vacuum. The residue was purified by chromatography(25-50% EtOAc/hexanes) to give 4-isochroman-5-yl-piperazine-1-carboxylicacid tert-butyl ester (0.89 g, 60%). MS (ES) m/z: 319.19 [M+1]. ¹H NMR(400 MHz, CDCl₃) δ 7.16 (t, J=7.8 Hz, 1 H), 6.88 (d, J=7.8 Hz, 1 H),6.75 (d, J=7.8 Hz, 1 H), 4.79 (s, 2 H), 3.94 (t, J=5.9 Hz, 2 H), 3.55(br s, 4 H), 2.86-2.80 (m, 4 H), 1.49 (s, 9 H).

To a solution of 4-isochroman-5-yl-piperazine-1-carboxylic acidtert-butyl ester (0.5 g, 1.57 mmol) in dry CH₂Cl₂ was added 3 mL of TFAat 0° C. dropwise. The resulting mixture was stirred at room temperaturefor 2 h. The evaporation of the solvent gave the third intermediatecompound (0.52 g, quantitative). MS (ES) m/z: 219.12[M+1]. ¹H NMR (400MHz, CDCl₃) δ 8.12 (br s, 1 H), 7.19 (t, J=7.3 Hz, 1 H), 6.95 (d, J=7.8Hz, 1 H), 6.82 (d, J=7.8 Hz, 1 H), 4.82 (s, 2H), 3.98(t, J=5.8 Hz, 2 H),3.54 (br s, 4 H), 3.21-3.19 (m, 4 H), 2.80 (t, J=5.4 Hz, 2 H).

A reductive amination procedure similar to Example A1′ was followedusing 1-isochroman-5-yl-piperazine to give the title compound (0.40 g,58%). MS (ES) m/z: 437.26 [M+1] (Exact mass: 436.25). ¹H NMR (400MHz,CDCl₃) δ 7.69(br s, 1 H), 7.36 (d, J=8.3 Hz, 1 H), 7.63 (d, J=7.3 Hz, 1H), 7.18 (t, J=7.8 Hz, 1 H), 6.92 (d, J=7.8 Hz, 1 H), 6.72 (d, J=7.3 Hz,1 H), 6.36 (d, J=7.3 Hz, 1 H), 4.80 (s, 2 H), 4.22 (t, J=6.3 Hz, 2 H),3.93 (t, J=5.4 Hz, 2 H), 2.95 (t, J=4.9 Hz, 4 H), 2.88-2.80 (m, 4 H),2.67-2.63 (m, 4 H), 2.47 (t, J=7.2 Hz, 4 H), 1.82-1.78 (m, 2 H),1.72-1.69 (m, 2 H).

Example A15′ Synthesis of7-[4-(4-Isochroman-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound 8-Bromo-isochroman and 6-Bromo-isochroman,was produced as follows: To a solution of1-bromo-3-[2-(2-methoxy-ethoxymethoxy)-ethyl]-benzene (2.8 g, 9.7 mmol)in 50 mL of CH₂Cl₂ was added a solution of TiCl₄ (14.5 mmol) in CH₂Cl₂dropwise at 0° C. The resulting mixture was stirred at the sametemperature for 1 h and treated with H₂O and CH₂Cl₂ . The organic layerwas washed with H₂O, dried over Na₂SO₄ and concentrated under vacuum.The residue was purified by chromatography (25% EtOAc/hexanes) to give1.8 g of a mixture of the first intermediate compounds,8-bromo-isochroman and 6-bromo-isochroman (˜1:4by HPLC) in 90% yield.

A second intermediate compound,4-lsochroman-8-yl-piperazine-1-carboxylic acid tert-butyl ester, wasproduced as follows: To a mixture of 8-bromo-isochroman and6-bromo-isochroman (1.8 g, 8.4 mmol), 1-boc-piperazine (1.9 g, 10.15mmol), 2-dicyclohexylphosphino biphenyl (0.12 g, 0.34 mmol), andPd(OAc)₂ (0.076 g, 0.34 mmol) in 15 mL of dry degassed toluene was addedNaOtBu (1.13 g, 11.8 mmol) at room temperature. The resulting mixturewas stirred at 80-90° C. for 1 h, cooled and passed through a pad ofcelite and the filtrate was concentrated under vacuum. The residue wassubjected to chromatography (10% EtOAc/hexanes) to give 0.2 g of thesecond intermediate compound, 4-isochroman-8-yl-piperazine-1-carboxylicacid tert-butyl ester, and 0.8 g of the regioisomer,4-isochroman-6-yl-piperazine-1-carboxylic acid tert-butyl ester, in 37%yield. Second intermediate compound: ¹H NMR (400 MHz, CDCl₃) δ 7.17 (t,J=7.8 Hz, 1 H), 6.90 (d, J=7.8 Hz, 2 H), 4.80 (s, 2 H), 3.96 (t, J=5.9Hz, 2 H), 3.53 (br s, 4 H), 2.87 (t, J=5.8 Hz, 4 H), 2.80 (t, J=4.4 Hz,4 H), 1.48 (s, 9 H). MS (ES) m/z: 319.19 [M+1] (Exact mass: 318.19).

A third intermediate compound, 1-lsochroman-8-yl-piperazine, wasproduced as follows: To a solution of4-isochroman-8-yl-piperazine-1-carboxylic acid tert-butyl ester (0.9 g,2.8 mmol) in 30 mL of dry CH₂Cl₂ was added 5 mL of TFA at 0° C.dropwise. The resulting mixture was stirred at room temperature for 2 h.The evaporation of the solvent gave 0.92 g of the third intermediatecompound in 98% yield. 1 H NMR (400 MHz, CDCl3) δ 8.18 (br s, 1 H) J7.25(t, J=8.0 Hz, 1 H), 7.02 (d, J=8.0 Hz, 2 H), 4.89 (s, 2 H), 4.07 (t,J=6.0 Hz, 2 H), 3.46 (br s, 4 H), 3.18-3.15 (m, 4 H), 2.94 (t, J=6.0 Hz,2 H). MS (ES) m/z: 219.13 [M+1] (Exact mass: 218.14).

A reductive amination procedure similar to Example A1′ was followedusing 1-isochroman-8-yl-piperazine to give the title compound (0.6 g,65%). MS (ES) m/z: 437.26 [M+1] (Exact mass: 436.25). ¹H NMR (400 MHz,CDCl₃) δ 7.69 (brs, 1 H), 7.35 (d, J=7.8 Hz, 1 H), 7.16 (t, J=7.8 Hz, 1H), 6.95 (d, J=7.8 Hz, 1 H), 6.88 (d, J=7.3 Hz, 1 H), 6.35 (d, J=8.3 Hz,1 H), 4.78 (s, 2 H), 4.22 (t, J=6.3 Hz, 2 H), 3.94 (t, J=5.8 Hz, 2 H),2.93 (t, J=4.9 Hz, 4 H), 2.88-2.84 (m, 4 H), 2.70-2.62 (m, 6 H), 2.55(t, J=7.8 Hz, 2 H), 1.82-1.77 (m, 2 H), 1.75-172 (m, 2 H).

Example A16′ Synthesis of7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine (WO 97/03067) togive the title compound. MS: APCl: M+1: 439.3 (Exact Mass: 438.23).

Example A17′ Synthesis of7-{4-[4-(3,4-Dihydro-2H-benzor[b][1,4]dioxepin-6-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

In a manner similar to that of other examples above,1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazine hydrochloride(J. Med. Chem. 1988, 31, 1934-1940) was coupled by reductive aminationto 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowed by typical workup and purification to give the intermediatecompound. MS: APCl: M+1: 453.6 (Exact Mass: 452.55).

Example A18′ Synthesis of7-{4-[4-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound,1-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine,was produced as follows: To the mixture of2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-ylamine (8.9 g, 40mmol) and bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester (14.5 g,60 mmol) in DMF (200 mL) was added NaH (3.2 g, 60% oil dispersion, 80mmol) at 0° C. and the resulting mixture was stirred at the sametemperature for 1.0 h. No reaction was observed by TLC. The mixture wasfurther stirred at room temperature for 4.0 h until LCMS indicated thestarting material disappeared. The reaction was quenched with aq. NH₄Cl,extracted with EtOAc, washed with brine, dried and concentrated. Theresidue was purified by flash chromatography (Et₃N: EtOAc:heptane/1:10:100) to afford4-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine-1-carboxylicacid tert-butyl ester (5.2 g, 33%) as colorless crystals.

A solution of4-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine-1-carboxylicacid tert-butyl ester (12.5 g, 0.0319 mol) in 1,4-dioxane (150 mL) wastreated with 4N HCl in 1,4-dioxane (100 mL) and the mixture was stirredat room temperature for 16 h, and then 35° C. for 2.0 h until LCMSindicated completion. The resulting solid was collected via filtration,rinsed with 1,4-dioxane, ether, and oven-dried to afford the titlecompound as the hydrochloride salt (8.9 g, 85%) as an off-white powder.

A reductive amination procedure similar to Example A1′ was followedusing1-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazinehydrochloride to give the title compound. MS: APCl: M+1: 511.1 (ExactMass: 510.19).

Example A19′ Synthesis of7-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound,1-(2,2-Difluoro-benzo[1,3]dioxol4-yl)-piperazine, was produced asfollows: To the mixture of 2,2-difluoro-benzo[1,3]dioxol-4-ylamine (27g, 0.156 mol) and bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester(75.5 g, 0.31 mol) in DMF (500 mL) was added NaH (15.6 g, 60% oildispersion, 0.39 mol) at 0° C. and the resulting mixture was stirred atroom temperature for 24 h until LCMS indicated the starting materialdisappeared. The reaction was quenched with aq. NH4Cl, extracted withEtOAc, washed with brine, dried and concentrated. The residue waspurified by flash chromatography (Et3N:EtOAc:heptane/1: 10:100) toafford 4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-piperazine-1-carboxylicacid tert-butyl ester (12.0 g, 22%) as colorless crystals.

A solution of4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-piperazine-1-carboxylic acidtert-butyl ester (9.9 g, 0.029 mol) in 1,4-dioxane (100 ml) was treatedwith 4N HCl in 1,4-dioxane (75 mL) and the mixture was stirred at roomtemperature for 20 h, and then 35-40° C. for 2.0 h until LCMS indicatedcompletion. The resulting solid was collected via filtration, rinsedwith ether, and oven-dried to afford the intermediate compound as thehydrochloride salt (7.8 g, 97%) as white powder.

A reductive amination procedure similar to Example A1′ was followedusing 1-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-piperazine hydrochloride togive the title compound. MS: APCl: M+1: 461.2 (Exact Mass: 460.19).

Example A20′ Synthesis of7-{4-[4-(4-Oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound8-Bromo-2,3-dihydrospiro[chromene-4,2′-[1,3]dioxolane], was produced asfollows: A mixture of 8-bromo-chroman-4-one (0.87 g, 3.8 mmol), ethyleneglycol (0.23 g, 3.8 mmol) and TsOH in benzene (50 mL) was refluxed usinga Dean-Stark apparatus for 16 h. It was cooled to RT, diluted with EtOAc(50 mL), washed with aqueous NaHCO₃, dried and concentrated to give thefirst intermediate compound (1.05 g). ¹H NMR (400 MHz, CDCl₃): δ 7.50(d, 1H), 7.40 (d, 1H), 6.90 (t, 1H), 4.30 (m, 2H), 4.10 (m, 2H), 4.10(m, 2H), 2.20 (m, 2H).

A second intermediate compound,4-(2,3-Dihydrospiro[chromene-4,2′-[1,3]dioxolan-8-yl])-piperazine-1-carboxylicacid tert-butyl ester, was produced as follows: Nitrogen gas was bubbledthrough a solution of8-bromo-2,3-dihydrospiro[chromene-4,2′-[1,3]dioxolane] (1.05 g, 3.89mmol), 1-Boc-piperazine (0.86 g, 4.67 mmol), Pd(OAc)₂ (88 mg) and2-dicyclohexylphosphino biphenyl (0.14 g) in toluene (40 mL) for 10 min.NaOtBu (0.52 g, 5.45 mmol) was added and the resulting mixture washeated at 110° C. for 3 h. The mixture was cooled to RT, diluted withEtOAC (40 mL) and filtered through a pad of celite. The filtrate wasconcentrated and the residue was purified by chromatography on silicagel to give the second intermediate compound (0.55 g, 38%). ¹H NMR (400MHz, CDCl₃): δ 7.15 (m, 1H), 6.90 (m, 2H), 4.47 (m, 2H), 4.22 (m, 2H),4.10 (m, 2H), 3.60 (m, 4H), 3.00 (m, 4H), 2.20 (m, 2H), 1.44 (s, 9H).

A third intermediate compound, 8-Piperazin-1-yl-chroman-4-one, wasproduced as follows: To a solution of4-(2,3-dihydrospiro[chromene4,2′-[1,3]dioxolan-8-yl])-piperazine-1-carboxylicacid tert-butyl ester (0.55 g, 1.46 mmol) in MeOH (10 mL) was addedconc. HCl (4 mL). The resulting mixture was stirred at room temperaturefor 16 h and concentrated under vacuum. The solid obtained was washedwith a small amount of MeOH and ether and dried to give the thirdintermediate compound (0.31 g, 69%).

A reductive amination procedure similar to Example A1′ was followedusing 8-piperazin-1-yl-chroman-4-one to give the title compound (0.32 g,83%). ¹H NMR (400 MHz, CDCl₃): δ 7.60 (d, 1H), 7.56 (d, 1H), 7.10 (d,1H), 6.96 (t, 1H), 6.39 (d,1H) 4.60 (t, 2H), 4.22 (t, 2H), 3.10 (br s,4H), 2.85 (m, 4H), 2.70 (m, 6H), 2.46 (m, 2H), 1.85-1.60 (m, 4H).

Example A21′ Synthesis of7-{4-[4-(3,3-Dimethyl-4-oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound 3-(2-Bromo-phenoxy)-2,2-dimethyl-propionicacid, was produced as follows: To a mixture of3-methanesulfonyloxy-2,2-dimethyl-propionic acid methyl ester (20.00 g,95.23 mmol) and 2-bromophenol (16.48 g, 95.23 mmol) in acetonitrile (200mL) was added Cs₂CO₃ (46.50 g, 142.80 mmol) and the mixture was heatedat 100° C. in a sealed flask overnight. The resulting suspension wasfiltered. The solvent was evaporated and the crude material waspartitioned between dichloromethane (100 mL) and water (100 mL). Theorganic layer was separated and the aqueous layer was extracted withdichloromethane (50 mL), dried over Na₂SO₄ and evaporation of thesolvent gave 3-(2-bromo-phenoxy)-2,2-dimethyl-propionic acid methylester (19.00 g, 70%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.55(d, 1H), 7.26-7.22 (m, 1H), 6.87-6.80 (m, 2H), 4.02 (s, 2H), 3.72 (s,3H), 1.40 (s, 6H).

To a solution of the methyl ester (19.00 g, 66.20 mmol) in THF:H₂O (4:1,50 mL) was added LiOH—H₂O (8.34 g, 198.60 mmol) and the mixture wasstirred at room temperature overnight. The organic solvent wasevaporated, and the aqueous layer was diluted with water (10 mL). The pHof the reaction mixture was adjusted to 3 using 1N HCl. The compound wasextracted with dichloromethane (2×100 mL). The organic layer was driedover Na₂SO₄ and evaporation of the solvent gave the first intermediatecompound (18.00 g, quantitative) as a colorless solid. ¹H NMR (400 MHz,CDCl₃): δ 7.52-7.50 (m, 1H), 7.26-7.22 (m,1H), 6.89-6.80 (m, 2H), 4.03(s, 2H), 1.41 (s, 6H).

A second intermediate compound, 8-Bromo-3,3-dir methyl-chroman-4-one,was produced as follows: To a solution of3-(2-bromo-phenoxy)-2,2-dimethyl-propionic acid (6.00 g, 21.98 mmol) inchlorobenzene (150 mL) was added Yb(OTf)₃ (1.36 g, 2.20 mmol) and themixture was heated at 190° C. in a sealed flask overnight. The resultingsuspension was filtered. The solvent was evaporated and the crudematerial was partitioned between diethyl ether (100 mL) and water (50mL). The organic layer was separated and the aqueous layer was extractedwith diethyl ether (50 mL), dried over Na₂SO₄ and evaporation of thesolvent gave the second intermediate compound (4.00 g, 71%) as a paleyellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, 1H), 6.75 (d, 1H),6.90-6.81 (m, 1H), 4.25 (s, 2H), 1.20 (s, 6H).

A third intermediate compound,4-(3,3-Dimethyl-4-oxo-chroman-8-yl)-piperazine-1-carboxylic acidtert-butyl ester, was produced as follows: To a mixture of8-bromo-3,3-dimethyl-chroman-4-one (1.60 g, 6.27 mmol) andBoc-piperazine (1.40 g, 7.53 mmol) in degassed toluene (30 mL) was addedpalladium acetate (0.14 g, 0.63 mmol),2-(di-tert-butylphosphino)biphenyl (0.37 g, 1.25 mmol) and sodiumt-butoxide (0.84 g, 8.78 mmol). The reaction mixture was heatedovernight at 100° C. The solvent was removed, and the compound waspurified by flash column chromatography using 10% ethyl acetate inhexanes to give the third intermediate compound (1.30 g, 58%). ¹H NMR(400 MHz, CDCl₃): δ 7.60 (d, 1H), 7.10 (br d, 1H), 6.95-6.90 (m, 1H),4.20 (s, 2H), 3.63-3.60 (m, 4H), 3.04-3.00 (m, 4H), 1.50 (s, 9H), 1.21(s, 6H).

A fourth intermediate compound,3,3-Dimethyl-8-piperazin-1-yl-chroman-4-one, was produced as follows: Asolution of 4-(3,3-dimethyl-4-oxo-chroman-8-yl)-piperazine-1-carboxylicacid tert-butyl ester (1.30 g, 3.61 mmol) in dichloromethane (10 mL) wastreated with trifluoroacetic acid (10 mL). The resulting mixture wasstirred at room temperature for 2 h. The brown solution was concentratedunder vacuum and diluted with water (20 mL) and pH was adjusted to 7using saturated NaHCO₃solution. The compound was extracted withdichloromethane (2×40 mL). The organic layer was dried over Na₂SO₄ andevaporation of the solvent gave the fourth intermediate compound (0.77g, 83%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.62 (d, 1H),7.11 (br d, 1H), 7.00-6.95 (m, 1H), 4.20 (s, 2H), 3.25-3.19 (m, 8H),1.22 (s, 6H).

A reductive amination procedure similar to Example A1′ was followedusing 3,3-dimethyl-8-piperazin-1-yl-chroman-4-one to give the titlecompound (0.41 g, 51%). ¹H NMR (400 MHz, CDCl₃) δ 7.73 (br s, 1H),7.60-7.58 (d, 1H), 7.37-7.35 (m, 1H), 7.11-7.09 (m, 1H), 6.99-6.95(m,1H), 6.35 (d, 1H), 4.24-4.21 (m, 4H), 3.11 (br, 4H), 2.87 (t, 2H),2.69-2.63 (m, 6H), 2.49 (t, 2H), 1.82-1.67 (m, 8H).

Example A22′ Synthesis of7-{4-[4-(3,3-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound 8-Bromo-3,3-dimethyl-chroman, was producedas follows: To a solution of 8-bromo-3,3-dimethyl-chroman-4-one (1.90 g,7.45 mmol) in BF₃-Et₂O (6 mL) was added Et₃SiH (5.19 g, 44.71 mmol) andthe mixture was heated at 90° C. in a sealed tube overnight. The solventwas evaporated and the crude material was partitioned between CH₂Cl₂ (20mL) and water (20 mL). The organic layer was separated and the aqueouslayer was extracted with CH₂Cl₂ (20 mL), dried over Na₂SO₄ andevaporation of the solvent gave the first intermediate compound (1.10 g,61%) as an oil. ¹H NMR (400 MHz, CDCl₃): δ 7.34 (d, 1H), 6.96 (d, 1H),6.74-6.70 (m, 1H), 3.86 (s, 2H), 2.57 (s, 2H), 1.03 (s, 6H).

A second intermediate compound,4-(3,3-Dimethyl-chroman-8-yl)-piperazine-1-carboxylic acid tert-butylester, was produced as follows: To a mixture of8-bromo-3,3-dimethyl-chroman (0.90 g, 3.73 mmol) and Boc-piperazine(0.83 g, 4.48 mmol) in degassed toluene (20 mL) was added palladiumacetate (0.08 g, 0.37 mmol), 2-(di-tert-butylphosphino)biphenyl (0.22 g,0.75 mmol) and sodium t-butoxide (0.50 g, 5.23 mmol). The reactionmixture was heated overnight at 100° C. The solvent was removed, and thecompound was purified by flash column chromatography using 10% ethylacetate in hexanes to give the second intermediate compound (0.65 g,50%). ¹H NMR (400MHz, CDCl₃): δ 6.83-6.71 (m, 3H), 3.83 (s, 2H),3.62-2.96 (br m, 4H), 2.99-2.96 (br m, 4H), 2.55 (s, 2H), 1.48 (s, 9H),1.03 (s, 6H).

A third intermediate compound, 1-(3,3-Dimethyl-chroman-8-yl)-piperazine,was produced as follows: A solution of4-(3,3-dimethyl-chroman-8-yl)-piperazine-1-carboxylic acid tert-butylester (0.65 g, 1.88 mmol) in dichloromethane (5 mL) was treated withtrifluoroacetic acid (5 mL). The resulting mixture was stirred at roomtemperature for 1 h. The brown solution was concentrated under vacuumand diluted with water (20 mL) and the pH was adjusted to 7 usingsaturated NaHCO₃ solution. The compound was extracted withdichloromethane (2×40 mL). The organic layer was dried over Na₂SO₄andevaporation of the solvent gave the third intermediate compound (0.55 g,quant.) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 6.84-6.74 (m,3H), 3.81 (s, 2H), 3.30-3.22 (m, 8H), 2.55 (s, 2H), 1.03 (s, 6H).

A reductive amination procedure similar to Example A1′ was followedusing 1-(3,3-dimethyl-chroman-8-yl)-piperazine to give the titlecompound (0.25 g, 53%). ¹H NMR (400 MHz, CDCl₃): δ 7.56 (br s, 1H), 7.39(d, 1H), 6.82-6.78 (m, 2H), 6.70 (br s,1H), 6.36 (d, 1H), 4.21 (m, 2H),3.81(s, 2H), 3.20-3.00 (br s, 3H), 2.82 (t, 2H), 2.70-2.60 (m, 6H), 2.55(s, 2H), 2.30-2.20 (br t, 2H), 1.82-1.63 (m, 4H), 1.03 (s, 6H).

Example A23′ Synthesis of7-[4-(4-Benzofuran-7-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 1-benzofuran-7-yl-piperazine to give the title compound. MS: APCl:M+1: 421.2 (Exact Mass: 420.22 ).

Example A24′ Synthesis of7-{4-[4-(1H-Indol-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 7-piperazin-1-yl-1H-indole to give the title compound. MS: APCl:M+1: 420.2 (Exact Mass: 419.23).

Example A25′ Synthesis of7-{4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 4-piperazin-1-yl-1H-indole. Purification by liquid chromatography(0-7% MeOH/CH₂Cl₂ ) gave the title compound as a foam. The foam wasdissolved in Et₂O and a solid crashed out (305 mg, 0.727 mmol, 43%). MS:APCl: M+1: 420.2 (Exact Mass: 419.23).

Example A26′ Synthesis of7-{4-[4-(1-Methyl-1H-indol-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 1-methyl-4-piperazin-1-yl-1H-indole. MS: APCl: M+1: (Exact Mass:433.25).

Example A27′ Synthesis of 7-{4-[4-(2-Methyl-1H-indol-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 2-methyl-4-piperazin-1-yl-1H-indole. Purification by liquidchromatography (6% MeOH/CH₂Cl₂) gave the title compound as a tan foam(618 mg, 1.43 mmol, 83%). MS: APCl: M+1: 434.2 (Exact Mass: 433.25).

Example A28′ Synthesis of7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 1-benzo[b]thiophen4-yl-piperazine. Purification by liquidchromatography (0-10% MeOH/CH₂Cl₂) gave the title compound as an oil.Et₂O was added and a solid crashed out to give a yellow solid (241 mg,0.552 mmol, 89%). MS: APCl: M+1: 437.2 (Exact Mass: 436.19).

Example A29′ Synthesis of 7-[4-(4-Benzo[1,2,5]oxadiazol-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 4-piperazin-1-yl-benzo[1,2,5]oxadiazole hydrochloride (Vogel,Martin; Karst, Uwe. (2001), DE 19936731) to give the title compound(0.395 g; 74%). MS: APCl: M+1: 423.2 (Exact mass: 422.21).

Example A30′ Synthesis of7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 4-piperazin-1-yl-benzo[1,2,5]thiadiazole (Lowe, John A., III.;Nagel, Arthur A. (1989), U.S. Pat. No. 4,831,031) to give the titlecompound (0.336 g; 60%). MS: APCl: M+1: 439.2 (Exact mass: 438.18).

Example A31′ Synthesis of7-{4-[4-(2-Trifluoromethyl-3H-benzoimidazol-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,4-Nitro-2-trifluoromethyl-1H-benzoimidazole, was produced as follows: Toa chilled flask containing 3-nitro-benzene-1,2-diamine (3.454 g, 22.557mmol, 1 eq) was added trifluoroacetic anhydride (19.33 g, 92.04 mmol, 4eq) drop wise. The suspension was stirred for two hours and then thelight brown solid was filtered off. To the solid was added toluene (55mL) and p-toluenesulfonic acid (10.13 g, 53.25 mmol, 2.361 eq) and themixture was heated at 120° C. for two hours. The reaction was cooled toroom temperature and diluted with ethyl acetate. The solution was washedwith 1 N NaOH and then brine. The organic solution was concentrated toprovide the first intermediate compound as a brown solid (4.622 g, 88%).MS: APCl: M+1: 232.0 (Exact Mass: 231.03).

A second intermediate compound,2-Trifluoromethyl-1H-benzoimidazol-4-ylamine, was produced as follows: Asolution of 4-nitro-2-trifluoromethyl-1H-benzoimidazole (3.73 g, 16.1mmol) in 100 mL (1: 1 THF:methanol) was hydrogenated using Ra/Ni. Thereaction was filtered and then concentrated to obtain secondintermediate compound (3.527 g, 100%). MS: APCl: M+1: 202.0 (Exact Mass:201.05).

A third intermediate compound,4-Piperazin-1-yl-2-trifluoromethyl-1H-benzoimidazole, was produced asfollows: To a reaction flask containing a mixture of2-trifluoromethyl-1H-benzoimidazol-4-ylamine (0.325 g, 1.618 mmol, 1 eq)and alumina (3.27 g, 32.1 mmol, 19.8 eq) was addedbis-(2-chloro-ethyl)-amine hydrochloride (0.600 g, 3.363 mmol, 2.1 eq).The reaction was heated to 140° C. for 6 hours. The reaction was cooledand treated with 10 mL of 1 N NaOH (1 mL) in methanol. The mixture wasfiltered and concentrated. Purification by chromatography on silica gel(0-40% MeOH/NH₄OH:CH₂Cl₂) afforded the third intermediate compound(0.181 g, 41%). MS: APCl: M+1: 271.0 (Exact Mass: 270.11).

To a suspension of4-(7-oxo-5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yloxy)-butyraldehyde(0.297 g, 1.266 mmol, 1.32 eq) and4-piperazin-1-yl-2-trifluoromethyl-1H-benzoimidazole (0.258 g, 0.953mmol, 1 eq) in dichloroethane (5 mL) was added NaBH(OAc)₃ (0.723 g,3.413 mmol, 3.58 eq). The slurry was allowed to stir overnight at roomtemperature (18 h). Analysis by HPLC showed reaction mostly complete.The mixture was diluted with Ethyl Acetate and quenched with saturatedNaHCO₃. The organic phase was then washed with brine, dried over Na₂SO₄,filtered and evaporated in vacuo. Purification by silica gelchromatography (2% MeOH/CH₂Cl₂) followed by formation of the HCl saltusing 1N HCl in ether provided the title compound (0.166 g, 35%). MS:APCl: M+1: 489.2 (Exact Mass: 488.21).

Example A32′ Synthesis of 7-{4-[4-(1-Methyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound,1-Methyl-5-piperazin-1-yl-1,2,3,4-tetrahydro-quinoline, was produced asfollows: To a stirred solution of4-(1,2,3,4-tetrahydro-quinolin-5-yl)-piperazine-1-carboxylic acidtert-butyl ester (1.30 g, 4.10 mmol) in THF-DMF (1: 1, 40 mL) was addedNaH (60% dispersion in oil, 0.58 g, 24.16 mmol) at room temperature. Theresulting mixture was stirred at room temperature for 1 h, cooled to 0°C. and iodomethane (1.75 g, 12.30 mmol) was added. The mixture wasstirred at room temperature overnight and diluted with ethyl acetate.Water was added and the organic layer was separated. The aqueous layerwas extracted with ethyl acetate. The combined organic extracts werewashed with water, brine, dried (Na₂SO₄) and the solvent was removed invacuo. The residue was purified on a silica gel column usinghexanes-ethyl acetate (3:1) as eluent to give4-(1-methyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazine-1-carboxylicacid tert-butyl ester (0.90 g, 66%) as a liquid. ¹H NMR (400MHz, CDCl₃):δ 7.10 (t, 1H), 6.40 (m, 2H), 3.50 (br s , 4H), 3.25 (t, 2H) 2.90 (s,3H), 2.80 (br s, 4H), 2.75 (t, 2H), 1.90 (t, 3H), 1.45 (s, 9H).

To a stirred solution of4-(1-methyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazine-1-carboxylicacid tert-butyl ester (0.90 g, 2.72 mmol) in dichloromethane (15 mL)cooled to 0° C., was added trifluoroacetic acid (3.10 g, 27.20 mmol).The resulting mixture was stirred at room temperature overnight and thesolvent was removed in vacuo to give the intermediate compound (0.90 g,97%) as a foam. ¹H NMR (400 MHz, CDCl₃): δ 9.60 (br s, 1H), 7.25 (d,1H), 6.90 (d, 1H), 6.79 (d, 1H), 3.39 (t, 2H), 3.30 (br s, 4H), 3.19 (brs, 4H), 3.10 (s, 3H), 2.78 (t, 2H), 2.15 (t, 2H), 1.65 (t, 2H). MS ES:m/z 232.12 (M+H)⁺ (Exact mass: 231.17).

A reductive amination procedure similar to Example A1′ was followedusing 1-methyl-5-piperazin-1-yl-1,2,3,4-tetrahydro-quinoline to give thetitle compound. ¹H NMR (400 MHz, CDCl₃): δ 12.95 (br s, 1H), 7.80 (br s,1H), 7.42 (d, 1H), 7.30 (d,1H), 7.15 (d, 1H), 6.39 (d, 1H), 4.28 (t,2H), 3.80-3.60(br, 4H), 3.45 (br s, 2H), 3.18 (s, 3H), 3.15 (br, 6H),2.85 (br s, t, 4H), 2.65(t, 2H), 2.18 (br, 4H), 1.85 (t, 2H). MS ES: m/z450.13 (M+H)⁺ (Exact mass: 449.28).

Example A33′ Synthesis of7-{4-[4-(1-Ethyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 1-ethyl-5-piperazin-1-yl-1,2,3,4-tetrahydro-quinoline to give thetitle compound. ¹H NMR (400 MHz, CDCl₃): δ 8.50 (s, 1H), 7.35 (d, 1H),7.00 (t, 1H), 6.28 (m, 2H), 4.30 (t, 2H), 3.60-2.20 (m, 8H), 2.95-2.40(m, 12H), 1.95-1.75 (m, 4H), 1.05 (t, 3H). MS ES: m/z 464.18 (M+H)⁺(Exact mass: 463.29).

Example A34′ Synthesis of7-[4-(4-Quinolin-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 8-piperazin-1-yl-quinoline. Purification by liquid chromatography(0-10% MeOH/CH₂Cl₂) gave the title compound as a foam (460 mg, 1.06mmol, 62%). MS: APCl: M+1: 432.2 (Exact Mass: 431.23).

Example A35′ Synthesis of7-[4-(4-Quinolin-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 5-piperazin-1-yl-quinoline. Purification by liquid chromatography(0-10% MeOH/CH₂Cl₂) gave the title compound as a white solid (517 mg,1.20 mmol, 70%). MS: APCl: M+1: 432.2 (Exact Mass: 431.23).

Example A36′ Synthesis of7-[4-(4-Isoquinolin-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 8-piperazin-1-yl-isoquinoline to give the title compound as ayellow foam. MS: APCl: M+1: 432.5 (Exact Mass: 431.23).

Example A37′ Synthesis of7-[4-(4-Isoquinolin-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 5-piperazin-1-yl-Isoquinoline to give the title compound as ayellow foam which was recrystallized from Et₂O to give a yellow solid.MS: APCl: M+1 : 432.2 (Exact Mass: 431.23).

Example A38′ Synthesis of7-{4-[4-(3-Fluoro-qiuinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound, 3-Fluoro-quinolin-5-ylamine and3-Fluoro-quinolin-8-ylamine, was produced as follows: 3-Fluoro-quinoline(2.808 g, 19.10 mmol) was cooled to 0° C. and sulfuric acid (15 mL) wasadded. To the mixture was added fuming nitric acid (1.21 mL, 1.81 g,29.0 mmol) dropwise. The mixture was warmed to room temperature andstirred for 1 hour. The mixture was poured into 200 mL ice, quenchedwith NaOH until basic and extracted with ethyl acetate (2×30 mL). Theorganic layers were combined and washed with brine (30 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give amixture of 3-fluoro-5-nitro-quinoline and 3-fluoro-8-nitro-quinoline(3.50 g, 95%) as a yellow solid.

The mixture of nitroquinolines was dissolved in ethyl acetate (40 mL)and 5% palladium on charcoal (800 mg) was added. The mixture was placedin a Parr apparatus and shaken under 40 psi hydrogen atmosphere for 1.5h. The mixture was filtered through celite, evaporated in vacuo and theresidue purified by column chromatography (gradient elution 3:1 to 1:1,hexanes/ethyl acetate) to yield 3-fluoro-quinolin-5-ylamine (1.79 g,61%) as a brown solid [¹H NMR (400 MHz, dmso-d₆) δ 8.80 (d, 1H), 8.40(d, 1H), 7.40 (t, 1H), 7.20 (d, 1H), 6.78 (d, 1H), 6.00 (s, 2H)] and3-fluoro-quinolin-8-ylamine (726 mg, 25%) [¹H NMR (400 MHz, CDCl₃) δ8.60 (s,1H), 7.64 (d, 1H), 7.38 (t, 1H), 7.10 (d, 1H), 6.84 (d, 1H),4.99 (s, 2H)].

A second intermediate compound, 3-Fluoro-5-piperazin-1-yl-quinoline, wasproduced as follows: 3-Fluoro-quinolin-5-ylamine (400 mg, 2.47 mmol),bis(2-chloroethyl)amine hydrochloride (485 mg, 2.72 mmol), sodium iodide(185 mg, 1.24 mmol) and diisopropylethylamine (0.22 mL, 160 mg, 1.24mmol) were all dissolved in a mixture of chlorobenzene (6 mL) and1-hexanol (1 mL). The mixture was heated at 140° C. overnight. Themixture was cooled and concentrated in vacuo. The residue was loadedonto silica gel and purified by column chromatography (1: 10:89,ammonium hydroxide/methanoydichloromethane) to yield the secondintermediate compound (301 mg, 53%) as a brown solid. ¹H NMR (400 MHz,dmso-d₆) δ 9.00 (s, 1H), 8.20 (d, 1H), 7.80 (d, 1H), 7.65 (t, 1H), 7.24(d, 1H), 3.30 (s, 1H), 3.20 (t, 4H), 3.05-3.00 (m, 4H).

A reductive amination procedure similar to Example A1′ was followedusing 3-fluoro-5-piperazin-1-yl-quinoline to give the title compound(273 mg, 57%). ¹H NMR (400 MHz, CDCl₃) δ 8.80 (s, 1H), 8.15 (d, 1H),7.80 (d, 1H), 7.62-7.50 (m, 2H), 7.40 (d, 1H), 7.20 (d, 1H), 6.40 (d,1H), 4.24 (t, 2H), 3.20-3.00 (m, 4H), 2.80 (t, 2H), 2.78-2.60 (m, 4H),2.60(t, 2H), 2.56 (t, 2H), 1.80-1.64 (m, 4H); MS ES+ 450.32 (M+H)⁺(Exact mass: 449.22).

Example A39′ Synthesis of7-{4-[4-(3-Fluoro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound, 3-Fluoro-8-piperazin-1-yl-quinoline, wasproduced as follows: 3-Fluoro-quinolin-8-ylamine (1.15 g, 7.10 mmol, seeprevious example), bis(2-chloroethyl)amine hydrochloride (1.39 g, 7.81mmol), sodium iodide (532 mg, 3.55 mmol) and diisopropylethylamine (0.62mL, 459 mg, 3.55 mmol) were all dissolved in a mixture of chlorobenzene(15 mL) and 1-hexanol (2.5 mL). The mixture was heated at 140° C. for 48hours. The mixture was cooled and concentrated in vacuo. The residue wasloaded onto silica gel and purified by column chromatography (1: 10:89,NH₄OH/methanol/dichloromethane) to yield the first intermediate compound(1.37 g, 83%) as a brown solid. ¹H NMR (400 MHz, dmso-d₆) δ 8.84 (s,1H), 8.20 (d, 1H), 7.60-7.52 (m, 2H), 7.15-7.10 (m, 1H), 3.60-3.20 (m,5H), 3.18-3.04 (m, 4H).

A reductive amination procedure similar to Example A1′ was followedusing 3-fluoro-8-piperazin-1-yl-quinoline to give the title compound(426 mg, 66%). ¹H NMR (400 MHz, dmso-d₆) δ 10.25 (s, 1H), 8.84 (s, 1H),8.20 (d, 1H), 7.54-7.40 (m, 3H), 7.14-7.00 (m, 1H), 6.40 (d, 1H), 4.20(t, 2H), 2.78 (t, 2H), 2.64-2.60 (m, 4H), 2.60-2.39 (m, 8H), 1.80-1.70(m, 2H), 1.70-1.58 (m, 2H), MS ES+ 450.22 (M+H)³⁰ (Exact mass: 449.22).

Example A40′ Synthesis of7-{4-[4-(2-Methyl-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 2-methyl-8-piperazin-1-yl-quinoline. Purification by liquidchromatography (0-10% MeOH/CH₂Cl₂) gave the title compound as a foam(530 mg, 1.19 mmol, 60% mmol). MS: APCl: M+1: 446.2 (Exact Mass:445.25).

Example A41′ Synthesis of7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound 8-Chloro-2-methoxy-quinoline, was producedas follows: To a suspension of 2,8-dichloro-quinoline (1.98 g,10.00mmol) in methanol (20 mL) was added NaOMe (0.81 g, 15.00 mmol) andthe reaction mixture was heated under reflux overnight. The solvent wasevaporated and the residue was dissolved in ethyl acetate (50 mL) andwashed with water (2×50 mL). The organic layer was dried (Na₂SO₄) andevaporated, and the crude product was purified by chromatography (10%EtOAc/Hexane) to give the first intermediate compound as a colorless oil(1.93 g, 99%). ¹H NMR (400 MHz, CDCl₃) δ: 8.00 (d, 2H), 7.70 (d, 1H),7.60 (d, 1H), 7.28 (t, 1H), 6.98(d, 1H), 4.10 (s, 3H).

A second intermediate compound,4-(2-Methoxy-quinolin-8-yl)-piperazine-1-carboxylic acid tert-butylester, was produced as follows: To an oven-dried flask, under nitrogen,was added Pd(OAc)₂ (0.04 g, 0.20 mmol) and2-(dicyclohexylphosphino)biphenyl (0.072 g, 0.20 mmol). The flask wasevacuated, filled with nitrogen, and then the following materials wereadded in this order: degassed toluene (10 mL),8-chloro-2-methoxy-quinoline (1.00 g, 5.14 mmol), 1-Boc-piperazine (1.15g, 6.18 mmol), and NaOtBu (0.69 g, 7.21 mmol). The mixture was stirredat 80° C. for 1.5 h. After cooling to room temperature, the mixture wasdiluted with ethyl acetate and filtered through a bed of celite. Thefiltrate was concentrated in vacuo. The crude material was purified bychromatography on silica gel (10% EtOAc/Hexane) to give the secondintermediate compound as a yellow oil (1.00 g, 56%). ¹H NMR (400 MHz,CDCl₃) δ: 7.98 (d, 2H), 7.40 (d, 1H), 7.30 (t, 1H), 7.10 (d, 1H),6.90(d, 1H), 4.05 (s, 3H), 3.75 (t, 4H), 3.38 (t, 4H), 1.50 (s, 9H).

A third intermediate compound, 2-Methoxy-8-piperazin-1-yl-quinoline, wasproduced as follows: To a solution of4-(2-methoxy-quinolin-8-yl)-piperazine-1-carboxylic acid tert-butylester (1.00 g, 2.90 mmol) in dichloromethane (20 mL) was addedtrifluoroacetic acid (4 mL) at 0° C. The reaction mixture was stirred atthis temperature for 3 h, and then allowed to warm to room temperature.The mixture was basified by addition of saturated NaHCO₃ and extractedwith dichloromethane (3×20 mL). The combined organic layer was dried(Na₂SO₄) and evaporated to give the third intermediate compound (0.70 9,99%). ¹H NMR (400 MHz, CDCl₃) δ: 7.98 (d, 2H), 7.40 (d, 1H), 7.30 (t,1H), 7.10 (d, 1H), 6.90 (d, 1H), 4.05 (s, 3H), 3.50 (m, 4H), 3.30 (m,4H).

A reductive amination procedure similar to Example A1′ was followedusing 2-methoxy-8-piperazin-1-yl-quinoline to give the title compound.¹H NMR (400 MHz, CDCl₃) δ: 7.98 (d, 2H), 7.58 (br s, 1H), 7.38 (d, 1H),7.30 (t,1H), 7.12 (d, 1H), 6.90 (d, 1H), 6.38 (d, 1H), 4.22 (t, 2H),4.05 (s, 3H), 2.82 (m, 6H), 2.62 (t, 2H), 2.50 (dd, 2H), 1.82 (m, 2H),1.78 (m, 2H).

Example A42′ Synthesis of7-{4-[4-(2-Ethoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

An intermediate compound, 2-Ethoxy-8-piperazin-1-yl-quinoline, wasproduced as follows: The title compound was prepared according to theprocedure detailed for 2-methoxy-8-piperazin-1-yl-quinoline above inExample A41′. ¹H NMR (400 MHz, CDCl₃) δ 9.30 (brs, 2H), 8.05 (d, 1H),7.55 (d, 1H), 7.40 (t, 1H), 7.30 (d, 1H), 6.96 (d, 1H), 4.50 (q, 2H),3.80 (m, 4H), 3.60(m, 4H), 1.50 (t, 3H).

A reductive amination procedure similar to Example A1′ was followedusing 2-ethoxy-8-piperazin-1-yl-quinoline to give the title compound(0.27 g, 80%). ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, 1H), 7.60 (brs, 1H),7.38 (m, 2H), 7.30 (t, 1H), 7.10 (d, 1H), 6.86 (d, 1H), 6.38 (d, 1H),4.58 (t, 2H), 4.28(t, 2H), 3.50 (brs, 4H), 2.90 (t, 2H), 2.82 (m, 4H),2.62 (t, 2H), 2.58(t, 2H), 1.90 (m, 2H), 1.80 (m, 2H), 1.50 (t, 3H); MS(ES): m/z: 476.25 (M+H)+ (Exact mass: 475.26).

Example A43′ Synthesis of7-{4-[4-(2-Methoxy-quinolin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound 5-Bromo-2-chloro-quinoline, was producedas follows: To a solution of 5-bromoquinoline (8.13 g, 39.27 mmol) inchloroform (70 mL) was added peroxyacetic acid and the mixture wasrefluxed for 3 hours. After cooling down, the mixture was poured intoice-water and basified by the addition of 4N NaOH aqueous solution to afinal pH of 10. The N-oxide was extracted with ethyl. acetate and dried(Na₂SO4). The solvent was evaporated to give the crude N-oxide as awhite solid (6.61 g). To the N-oxide (5.20 g, 23.31 mmol) at −10° C. wascarefully added POCl₃ (40 mL, highly exothermic). The mixture was thenstirred at room temperature for 10 min and heated at 100° C. for 3hours. The excess of POCl₃was removed under vacuum. The residue wasdissolved in dichloromethane, poured into ice-water, and the pH wasadjusted to 8. The aqueous layer was extracted with dichloromethane. Thecombined organic layers were dried and evaporated. The crude product waspurified by chromatography (5% EtOAc/Hexane) to give the firstintermediate compound as a white solid (1.70 g, 30%). ¹H NMR (400 MHz,CDCl₃) δ: 8.50 (d, 1H), 8.05 (d, 1H), 7.85 (d,1H), 7.60 (dd,1H), 7.50(d,1H).

A second intermediate compound, 5-Bromo-2-methoxy-quinoline, wasproduced as follows: To a suspension of 5-bromo-2-chloro-quinoline (0.99g, 4.10 mmol) in methanol (20 mL) was added NaOMe (0.27 g, 4.73 mmol)and the reaction mixture was heated under reflux overnight. The solventwas evaporated and the residue was dissolved in ethyl acetate (50 mL).The organics were washed with water (2×50 mL), dried (Na₂SO₄) andevaporated. The crude product was purified by chromatography (5%EtOAc/Hexane) to give the second intermediate compound as white crystals(0.79 g, 82%). ¹H NMR (400 MHz, CDCl₃) δ: 8.40 (d, 1H), 7.85 (d, 1H),7.65 (d, 1H), 7.45 (dd, 1H), 7.00 (d, 1H), 4.10 (s, 3H).

A third intermediate compound, 2-Methoxy-5-piperazin-1-yl-quinoline, wasproduced as follows: To an oven-dried flask, under nitrogen, was addedPd(OAc)₂ (0.03 g, 0.13 mmol) and 2-(dicyclohexylphosphino)biphenyl(0.045 g, 0.13 mmol). The flask was evacuated and refilled withnitrogen. The following materials were added in the following order:degassed toluene (10 mL), 5-bromo-2-methoxy-quinoline (0.76 g, 3.23mmol), 1-Boc-piperazine (0.72 g, 3.87 mmol), and NaOtBu (0.43 g, 4.52mmol). The mixture was stirred at 80° C. for 1.5 h. After cooling toroom temperature, the mixture was diluted with ethyl acetate andfiltered through celite. The filtrate was concentrated in vaccuo andpurified by chromatography on silica gel (10% EtOAc/Hexane) to give4-(2-methoxy-quinolin-5-yl)-piperazine-1-carboxylic acid tert-butylester as a yellowish solid (0.73 g, 66%). ¹H NMR (400 MHz, CDCl₃) δ:8.35 (d, 1H), 7.60 (m, 2H), 7.00 (d, 1H), 6.90 (d, 1H), 4.05 (s, 3H),3.75 (m, 4H), 3.00 (m, 4H), 1.50 (s, 9H).

To a solution of 4-(2-methoxy-quinolin-5-yl)-piperazine-1-carboxylicacid tert-butyl ester (0.73 g, 2.14 mmol) in dichloromethane (4.0 mL)was added trifluoroacetic acid (16 mL) at 0° C. The reaction mixture wasstirred for 3 h, and was allowed to warm to room temperature during thistime. The mixture was evaporated and the residue was treated withdiethyl ether. The precipitate was filtered and washed with ether togive the title compound (0.75 g, 95%). ¹H NMR (400 MHz, CDCl₃) δ: 9.90(br.s, 2H), 8.25 (d, 1H), 7.65 (d, 1H), 7.58 (t, 1H), 7.10 (d, 1H), 6.90(d,1H), 4.05 (s, 3H), 3.50 (m, 4H), 3.35 (m, 4H).

A reductive amination procedure similar to Example A1′ was followedusing 2-methoxy-5-piperazin-1-yl-quinoline to give the title compound(0.38 g, 99%). ¹H NMR (400 MHz, CDCl₃) δ: 8.35 (d, 1H), 7.60 (br.s, 1H),7.55 (dd, 1H), 7.40 (d, 1H), 7.00 (d, 1H), 6.85 (d, 1H), 6.38 (d, 1H),4.25(t, 2H), 4.05 (s, 3H), 3.10 (br.s, 4H), 2.90 (t, 2H), 2.80 (br.s,4H), 2.70 (t, 2H), 2.55 (t, 2H), 1.82 (m, 2H), 1.78 (m, 2H).

Example A44′ Synthesis of7-[4-(4-Quinoxalin-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound Trifluoro-methanesulfonic acidquinoxalin-5-yl ester, was produced as follows: To a solution ofquinoxalin-5-ol (3.97 g, 27.2 mmol, prepared according to J. Org. Chem.1951, 16, 438-442) in CH₂Cl₂ (110 mL) cooled to 0° C. was added Et₃N(7.6 mL, 54.3 mmol) followed by trifluoromethanesulfonic anhydride (6.0mL, 35.4 mmol). The rxn smoked briefly and was stirred at 0° C. for 1 h.The reaction was quenched with sat. NaHCO₃at 0° C. and warmed to RT. Thelayers were separated and the aqueous layer was extracted with CH2Cl2.The combined organic layer was washed with water and brine, dried overNa₂SO₄ and concentrated to give an organic brown solid. The crudematerial was absorbed onto SiO₂ and purified by LC (20% EtOAc/Hexanes)to give the first intermediate compound as a light orange solid (6.51 g,23.4 mmol, 86%). MS: APCl: M+1: 279.0 (Exact Mass: 278.00).

A second intermediate compound,4-Quinoxalin-5-yl-piperazine-1-carboxylic acid tert-butyl ester, wasproduced as follows: A solution of trifluoro-methanesulfonic acidquinoxalin-5-yl ester (4.23 g, 15.2 mmol) in dry DME (30 mL) wasdegassed for 10 min by blowing nitrogen into the solution. This solutionwas then added via cannula to a flask containing Boc-piperazine (3.54 g,19.00 mmol), K₃PO₄ (4.52 g, 21.3 mmol), Pd₂(dba)₃ (348 mg, 0.380 mmol,2.5 mol %) and 2-(di-t-butylphosphino)biphenyl (227 mg, 0.760 mmol, 5mol %) under nitrogen. The reaction mixture was heated at 80° C.overnight (20 h). MS showed a large product peak. The reaction wasallowed to cool to room temperature and Et₂O was added. The mixture wasfiltered through Celite washing with Et₂O. The filtrate was washed with0.5 M citric acid (2×, to remove excess Boc-piperazine) and once withbrine, dried over Na₂SO₄ and concentrated to give a dark red oil.Purification by LC (40% EtOAc/Hexanes) gave the product as a red oilwhich foamed on the pump (2.68 g, 8.52 mmol, 56%). MS: APCl: M+1: 315.2(Exact Mass: 314.17).

A third intermediate compound, 5-Piperazin-1-yl-quinoxaline, wasproduced as follows: To a solution of4-quinoxalin-5-yl-piperazine-1-carboxylic acid tert-butyl ester (2.65 g,8.43 mmol) in CH₂Cl₂ (15 mL) cooled to 0° C. was added TFA (15 mL). Thereaction was warmed to room temperature and stirred for 90 min. Themixture was concentrated and the remaining TFA was neutralized by adding10% MeOH/CH2Cl2 with 1% NH₄OH. SiO₂ was added and the mixture wasconcentrated. Purification by LC (10% MeOH/CH₂Cl₂ with 1% NH₄OH) gavethe third intermediate compound as an orange solid (1.65 g, 7.70 mmol,91%). MS: APCl: M+1: 215.2 (Exact Mass: 214.12).

A reductive amination procedure similar to Example A1′ was followedusing 5-piperazin-1-yl-quinoxaline to give the title compound. MS: APCl:M+1: 433.3 (Exact Mass: 432.23).

Example A45′ Synthesis of7-{4-[4-(2-Dimethylamino-quinolin-8-yl)-pierazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound (8-Chloro-quinolin-2-yl)-dimethyl-amine,was produced as follows: To a suspension of 2,8-dichloro-quinoline (5.00g, 25.2 mmol) in a water/dioxane solution (69 mL, 10:1) was added anaqueous solution of Na₂CO₃ (2N, 38 mL, 76 mmol) and dimethylaminehydrochloride (4.12 g, 50.5 mmol). The reaction mixture was heated at160° C. for 1.5 h in a microwave. The reaction was extracted with CH₂Cl₂(2×), dried (Na₂SO₄) and evaporated, and the crude product was purifiedby chromatography (2-20% EtOAc/Hexane) to give the first intermediatecompound as a faint yellow solid (4.22 g, 81%). MS: APCl: M+1: 207.0(Exact mass: 206.06).

A second intermediate compound,4-(2-Dimethylamino-quinolin-8-yl)-piperazine-1-carboxylic acidtert-butyl ester, was produced as follows: To an oven-dried flask, undernitrogen, was added Pd₂ (dba)₃ (0.111 g, 0.121 mmol) and(2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (0.190 g,0.484mmol). The flask was evacuated, filled with nitrogen, and then thefollowing materials were added in this order: degassed toluene (14 mL),(8-chloro-quinolin-2-yl)-dimethyl-amine (1.00 g, 5.14 mmol),1-Boc-piperazine (1.80 g, 9.68 mmol), and Cs₂CO₃ (2.21 g, 6.77 mmol).The mixture was stirred at 105° C. for 19 h. Another 5 mol % of thecatalyst was added and heating was continued for an additional 18 h.After cooling to room temperature, the mixture was diluted and filteredthrough a bed of celite. The filtrate was concentrated in vacuo. Thecrude material was purified by chromatography on silica gel (3-40%EtOAc/Hexane) to give the second intermediate compound as yellow foam(1.26 g, 73%). MS: APCl: M+1: 357.2 (Exact mass: 356.22).

A third intermediate compound,Dimethyl-(8-piperazin-1-yl-quinolin-2-yl)-amine, was produced asfollows: To a solution of4-(2-dimethylamino-quinolin-8-yl)-piperazine-1-carboxylic acidtert-butyl ester (1.244 g, 3.63 mmol) in dichloromethane (35 mL) wasadded trifluoroacetic acid (10 mL) at 0° C. The reaction mixture wasstirred at this temperature for 1.5 h, and then allowed to warm to roomtemperature. The volatiles were removed in vacuo and the crude oil wastaken up in CH₂Cl₂, and washed with 2N KOH, dried (Na₂SO₄) andevaporated to give the third intermediate compound (0.895 g, >99%). MS:APCl: M+1: 257.1 (Exact mass: 256.17).

A reductive amination procedure similar to Example A1′ was followedusing dimethyl-(8-piperazin-1-yl-quinolin-2-yl)-amine to give the titlecompound (0.314 g; 79%). MS: APCl: M+1: 475.2 (Exact mass: 474.27).

Example A46′ Synthesis of7-{4-[4-(2-Methylamino-quinolin-8-yl)-pierazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound (8-Chloro-quinolin-2-yl)-methyl-amine, wasproduced as follows: To a suspension of 2,8-dichloro-quinoline (5.00 g,25.2 mmol) in a water/dioxane solution (69 mL, 10: 1) was added anaqueous solution of Na₂CO₃ (2N, 25.2 mL, 50.5 mmol) and aqueousmethylamine (40% w/w, 5.4 g, 63 mmol). The reaction mixture was heatedat 160° C. for 1.5 h in a microwave. The reaction was extracted withCH₂Cl₂ (2×), dried (Na₂SO₄) and evaporated, and the crude product waspurified by chromatography (2-20% EtOAc/Hexane) to give the firstintermediate compound as a light yellow solid (3.69 g, 76%). MS: APCl:M+1: 193.0 (Exact mass: 192.05).

A second intermediate compound,4-(2-methylamino-quinolin-8-yl)-piperazine-1-carboxylic acid tert-butylester, was produced as follows: To an oven-dried flask, under nitrogen,was added Pd₂ (dba)₃ (0.238 g, 0.260 mmol) and(2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (0.409 g, 1.04mmol). The flask was evacuated, filled with nitrogen, and then thefollowing materials were added in this order: degassed toluene (30 mL),(8-chloro-quinolin-2-yl)-methyl-amine (2.00 g, 10.4 mmol),1-Boc-piperazine (3.87 g, 20.8 mmol), and Cs₂CO₃ (4.74 g, 14.5 mmol).The mixture was stirred at 105° C. for 19 h. After cooling to roomtemperature, the mixture was diluted and filtered through a bed ofcelite. The filtrate was concentrated in vacuo. The crude material waspurified by chromatography on silica gel (3-50% EtOAc/Hexane) to givethe second intermediate compound as light orange oil (0.751 g, 21%). MS:APCl: M+1: 343.3 (Exact mass: 342.21).

A third intermediate compound,Dimethyl-(8-piperazin-1-yl-quinolin-2-yl)-amine, was produced asfollows: To a solution of4-(2-methylamino-quinolin-8-yl)-piperazine-1-carboxylic acid tert-butylester (0.751 g, 2.19 mmol) in dichloromethane (29 mL) was addedtrifluoroacetic acid (10 mL) at 0° C. The reaction mixture was stirredat this temperature for 1 h, and then allowed to warm to roomtemperature. The volatiles were removed in vacuo and the crude oil wastaken up in CH₂Cl₂, and washed with 2N KOH, dried (Na₂SO₄) andevaporated to give the third intermediate compound (0.510 g, 96%). MS:APCl: M+1: 243.1 (Exact mass: 242.15).

A reductive amination procedure similar to Example A1′ was followedusing methyl-(8-piperazin-1-yl-quinolin-2-yl)-amine to give the titlecompound (0.081 g; 28%). MS: APCl: M+1: 461.3 (Exact mass: 460.26).

Example A47′ Synthesis of7-{4-[4-(2-Oxo-1,2-dihydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-1,8]naphthyridin-2-one

In a manner similar to that of other examples above,8-piperazin-1-yl-1H-quinolin-2-one hydrochloride (Chem. Pharm. Bull.1984, 32, 2100-2110) was coupled by reductive amination to4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowed by typical workup and purification to give the title compound.MS: APCl: M+1: 448.2 (Exact Mass: 447.23).

Example A48′ Synthesis of7-{4-[4-(2-Oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

In a manner similar to that of other examples above,8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride (Chem.Pharm. Bull. 1984, 32, 2100-2110) was coupled by reductive amination to4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowed by typical workup and purification to give the title compound.MS: APCl: M+1: 450.2 (Exact Mass: 449.24).

Example A49′ Synthesis of7-{4-[4-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound,4-(2-Oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazine-1-carboxylic acidtert-butyl ester, was produced as follows: To dichloromethane (75 mL)was added 8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride(10.8 mmol), diisopropylethylamine (1.95 mL, 11.2 mmol) anddi-t-butylcarbonate (9.20 g, 9.33 mmol) followed by stirring for 16hours at 25° C. The mixture was washed consecutively with 1N citricacid, saturated sodium bicarbonate and brine. The organic phase wasdried over sodium sulfate, filtered and evaporated to give the firstintermediate compound (2.78 g), mp 117-178° C.

A second intermediate compound,1-Methyl-8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride,was produced as follows: To a solution of4-(2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazine-1-carboxylic acidtert-butyl ester (2.5 g, 7.54 mmol) in THF (45 mL) cooled to −50° C. wasadded a solution of potassium t-butoxide, 1M in THF (8.3 mL, 8.30 mmol).After stirring for 15 minutes, methyl iodide (0.47 mL, 7.54 mmol) wasadded followed by stirring for 16 hours at 25° C. The mixture wasevaporated and the residue was taken up into dichloromethane. Thesolution was washed consecutively with 1N citric acid, saturated sodiumbicarbonate and brine. The organic phase was dried over sodium sulfate,filtered and evaporated to give a white foam, which was purified bychromatography on silica gel eluting with a gradient of dichloromethaneand ethyl acetate. Evaporation of the appropriate fractions gave4-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazine-1-carboxylicacid tert-butyl ester (2.1 g).

To a mixture of dichloromethane (45 mL) and diethyl ether (5 mL) wasadded 4-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.1 g, 6.08 mmol), followed bypurging with anhydrous HCl gas intermittently over several hours untilthe starting material was consumed. The mixture was evaporated to asolid, triturated with diethyl ether and dried in vacuo to give thesecond intermediate compound as a pale yellow solid (1.75 g).

In a manner similar to that of other examples above,1-methyl-8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloridewas coupled by reductive amination to4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowed by typical workup and purification to give the title compound.MS: APCl: M+1: 464.6 (Exact Mass: 463.26).

Example B1′ Synthesis of7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

A first intermediate compound,2-Benzyloxy-7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-[1,8]naphthyridine,was produced as follows: To a solution of4-(tetrahydro-pyran-2-yloxy)-1-butanol (3.27 g, 18.8 mmol, 1.2 equiv) inTHF (20 mL) cooled to 0° C. was added KOtBu (1M in THF, 18 mL, 18 mmol,1.15 equiv). The solution was stirred at 0° C. for 20 min and then addedvia cannula to a suspension of 2-benzyloxy-7-chloro-[1,8]naphthyridine(4.24 g, 15.66 mmol) in THF (50 mL) cooled to 0° C. The reaction turnedorange and became homogenous. After 30 min at 0° C, saturated NH₄Cl andH₂O were added to quench the reaction. The mixture was extracted withEtOAc. The organic layer was washed with saturated NaHCO₃, H₂O andbrine, dried over Na₂SO₄ and concentrated. The crude was absorbed ontoSiO₂ and purified by liquid chromatography (20-30% EtOAc/Hexanes) togive the first intermediate compound as a pale yellow oil (3.71 g, 9.08mmol, 58%). MS: APCl: M+1: 409.2 (Exact Mass: 408.20).

A second intermediate compound,7-(4-Hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one, was produced asfollows:2-Benzyloxy-7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-[1,8]naphthyridine(620 mg, 1.52 mmol) was hydrogenated using 5% Pd/C in MeOH for 40 min.The reaction was filtered and concentrated. The residue was dissolved inEtOH (5 mL) and PPTS (25 mg, 0.10 mmol) was added. The mixture washeated at 60° C. overnight. The reaction was concentrated and purifiedby liquid chromatography (6% MeOH/CH₂Cl₂) to give the secondintermediate compound as a white solid (282 mg, 1.20 mmol, 79%). MS:APCl: M+1: 235.1 (Exact Mass: 234.10).

This intermediate was also prepared using the following procedure: To asuspension of 60% NaH (83.6 g, 2.09 mol) in NMP (1 L) was added dry1,4-butanediol (300 mL, 3.39 mol, concentrated from toluene) dropwise tocontrol foaming. The reaction temperature increased to 50° C. and themixture was stirred at 60° C. for 15 min.7-Chloro-1H-[1,8]naphthyridin-2-one (146 g, 0.813 mol) was added withstirring and the reaction was heated at 68° C. for 20 h. CH₃CN (5 L) wasadded and the mixture was filtered and the filter cake was washed withCH₃CN (500 mL) and THF (500 mL). The filter cake was reslurried with THF(3 L) and 3N HCl in MeOH (290 mL, 0.870 mol) was added. The mixture washeated at 60° C. for 1 h and then filtered through celite washing withTHF (1 L). The filtrate was concentrated to a volume of 500 mL and THF(1.5 L), Darco (10 g) and magnesol (100 mL) was added. The mixture wasstirred at 40° C. for 30 min and then filtered washing with THF (500mL). The filtrate was concentrated to 500 mL, CH₃CN was added and themixture was concentrated to 1 L. The resulting solid was filtered,washed with CH₃CN (200 mL) and Et₂O (300 mL) and dried at 50° C. toyield the second intermediate compound (101 g, 53%). The filtrate uponstanding gave additional crystals, which were collected by filtration,washed and dried as before to give additional second intermediatecompound (17 g, total yield of 62%).

A third intermediate compound,4-(7-Oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde, wasproduced as follows: Using Swern oxidation: To a solution of oxalylchloride (0.12 mL, 1.32 mmol, 1.1 equiv) in CH2Cl2 (2.5 mL) cooled to−78° C. was added DMSO (0.18 mL, 2.6 mmol). The reaction was stirred for5 min and then 7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one (282 mg,1.20 mmol) was added as a solution in CH2Cl2 (4.5 mL) and DMSO (1.2 mL)via cannula over 5 min. The DMSO was necessary to dissolve the alcohol.The reaction was stirred for 15 min and Et3N (0.83 mL, 6.0 mmol, 5equiv) was added. The reaction turned cloudy. The reaction was allowedto stir at −78° C. for 10 min and then warmed to RT. After 30 min at RT,H2O was added and the mixture was extracted with CH2Cl2. The organiclayer was washed with brine, dried over MgSO4 and concentrated to givethe third intermediate compound as a light brown oil (340 mg), which wasused in the next reaction. MS: APCl: M+1: 233.1 (Exact Mass: 232.08).

Using IBX oxidation: To a solution of7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one (223 mg, 0.952 mmol) inDMSO (3 mL) was added a solution of IBX (400 mg, 1.43 mmol) in DMSO (4.8mL, 0.3 M). The reaction was stirred at room temperature for 6 h, cooledto 0° C. and quenched with 5% NaHCO3. The mixture was extracted withCH2Cl2 (4×). The organic layer was washed with 5% NaHCO3, dried overMgSO4 and concentrated to give the third intermediate compound as a paleyellow solid (175 mg, 0.754 mmol, 79%). MS: APCl: M+1: 233.1 (ExactMass: 232.08).

A mixture of4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (300 mg,1.29 mmol) and 1-chroman-8-yl-piperazine bishydrochloride (395 mg, 1.36mmol) were suspended in DCE (8 mL)/DMF (1 mL) and Et3N (0.54 mL, 3.88mmol) was added. After about 10 min, NaBH(OAc)3 (356 mg, 1.68 mmol) wasadded and the reaction was stirred at room temperature for 2 h. Thereaction was quenched with saturated NaHCO3 and extracted with EtOAc.The organic layer was washed with saturated NaHCO3 and brine, dried overNa2SO4 and concentrated. Purification by liquid chromatography (5%MeOH/CH2Cl2 with 0.5% NH4OH) gave the title compound as a white foam(364 mg, 0.838 mmol, 65%). The foam was dissolved in THF/Et2O and 1N HClin Et2O (0.84 mL) was added. The resulting precipitate was collected byfiltration, washed with Et2O and dried to give a white solid (368 mg).MS: APCl: M+1: 435.2 (Exact mass: 434.23).

Example B2′ Synthesis of7-{4-[4-(2,2-Dimethyl-2H-chromen-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-(2,2-dimethyl-2H-chromen-8-yl)-piperazine to give the title compound.MS: APCl: M+1: 461.2 (Exact mass: 460.25).

Example B3′ Synthesis of7-{4-[4-(2,2-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-(2,2-dimethyl-chroman-8-yl)-piperazine to give the title compound. MS:APCl: M+i: 463.2 (Exact mass: 462.26).

Example B4′ Synthesis of7-{4-[4-(2-Methyl-2H-chromen-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-(2-methyl-2H-chromen-8-yl)-piperazine to give the title compound. MS:APCl: M+1: 447.3 (Exact mass: 446.23).

Example B5′ Synthesis of7-{4-[4-(2-Methyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-(2-methyl-chroman-8-yl)-piperazine to give the title compound. MS:APCl: M+1: 449.3 (Exact mass: 448.25).

Example B6′ Synthesis of7-{4-[4-(Spiro[chromene-2,1′-cyclopentan]-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-spiro[chromene-2,1′-cyclopentan]-8-ylpiperazine to give the titlecompound. MS: APCl: M+1: 487.2 (Exact mass: 486.26).

Example B7′ Synthesis of7-{4-[4-(3,4-Dihydrospiro[chromene-2,1′-cyclopentan]-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-(3,4-dihydrospiro[chromene-2,1′-cyclopentan]-8-yl)piperazine to givethe title compound. MS: APCl: M+1: 489.3 (Exact mass: 488.28).

Example B8′ Synthesis of7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-(2,3-dihydro-benzofuran-7-yl)-piperazine to give the title compound.MS: APCl: M+1: 421.2 (Exact mass: 420.22).

Example B9′ Synthesis of7-{4-[4-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazine to give thetitle compound. MS: APCl: M+1: 449.2 (Exact mass: 448.25).

Example B10′ Synthesis of7-[4-(4-Chroman-5-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-chroman-5-yl-piperazine to give the title compound. MS: APCl: M+1:435.3(Exact mass: 434.23).

Example B11′ Synthesis of7-{4-[4-(2,3-Dihydro-benzofuran-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-(2,3-dihydro-benzofuran-4-yl)-piperazine to give the title compound.MS: APCl: M+1: 421.2 (Exact mass: 420.22).

Example B12′ Synthesis of7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine to give the titlecompound. MS: APCl: M+1: 437.2 (Exact mass: 436.21).

Example B13′ Synthesis of7-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-piperazine to give the titlecompound. MS: APCl: M+1: 459.2 (Exact mass: 458.18).

Example B14′ Synthesis of7-{4-[4-(1,3-Dihydro-isobenzofuran-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

To a suspension of4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.257 g,1.107 mmol, 1.1 eq) and 1-(1,3-dihydro-isobenzofuran-4-yl)-piperazine(0.204 g, 0.998 mmol, 1 eq) in dichloroethane (5 mL) was addedNaBH(OAc)₃ (0.433 g, 2.043 mmol, 1.84 eq). The slurry was allowed tostir overnight at room temperature (18 h). The mixture was diluted withEtOAc and quenched with saturated NaHCO₃. The organic phase was thenwashed with brine, dried over Na₂SO₄, filtered and evaporated in vacuo.Purification by silica gel chromatography (2% MeOH/CH₂Cl₂) followed byformation of the HCl salt using 1N HCl in ether provided the titlecompound (0.064 g, 12%). CHN Found: C, 64.37; H, 6.54; N, 12.13. Thiscalculates out for C₂₄H₂₈N₄O₃×0.74 HCl.

Example B15′ Synthesis of7-{4-[4-(4-Oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using8-piperazin-1-yl-chroman-4-one to give the title compound (0.22 g, 48%).¹H NMR (400 MHz, CDCl₃): δ 9.00 (br s, 1H), 7.75 (d, 1H), 7.60 (m, 2H),7.10 (d, 1H), 7.00 (t, 1H), 6.60 (d, 1H), 6.50 (d, 1H), 4.60 (t, 2H),4.40 (t, 2H), 3.10 (br s, 4H), 2.80-2.40 (m, 8H), 1.90-1.70 (m, 4H).

Example B16′ Synthesis of7-{4-[4-(3,3-Dimethyl-4-oxo-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using3,3-dimethyl-8-piperazin-1-yl-chroman-4-one to give the title compound(0.30 g, 55%). ¹H NMR (400 MHz, CDCl₃): δ 9.90 (br s, 1H), 7.71 (d, 1H),7.63 (d, 1H), 7.60-7.58 (m, 1H), 7.10 (d, 1H), 6.98-6.94 (m, 1H), 6.60(d, 1H), 6.54 (d 1H), 4.20 (t, 2H), 4.22 (s, 2H), 3.12 (br s, 4H), 2.72(br s, 4H), 2.52 (t, 2H), 1.87-1.71 (m, 4H), 1.21 (s, 6H).

Example B17′ Synthesis of7-{4-[4-(3,3-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-(3,3-dimethyl-chroman-8-yl)-piperazine to give the title compound(0.30 g, 54%). ¹H NMR (400 MHz, CDCl₃) δ 9.39 (br s, 1H), 7.71 (d, 1H),7.63 (d, 1H), 6.80-6.78 (m, 2H), 6.71-6.69 (m, 1H), 6.58 (d, 1H), 6.52(d, 1H), 4.38 (t, 2H), 3.82 (s, 2H), 3.09 (br s, 4H), 2.69 (br s, 4H),2.55 (s, 2H), 2.48 (t, 2H), 1.86-1.66 (m, 6H), 1.02 (s, 6H).

Example B18′ Synthesis of7-[4-(4-lsochroman-5-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-isochroman-5-yl-piperazine to give the title compound. ¹H NMR (400MHz, CDCl₃) δ 9.05 (br s, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.63 (d, J=9.7Hz, 1H), 7.16 (t, J=7.8 Hz, 1 H), 6.92 (d, J=7.8 Hz, 1 H), 6.72 (d,J=7.3 Hz, 1 H), 6.60 (dd, J=1.0 Hz, J=8.3 Hz, 1 H), 6.52 (d, J=9.8 Hz, 1H), 4.80 (s, 2 H), 4.39 (t, J=6.3 Hz, 2 H), 3.93 (t, J=5.8 Hz, 2 H),2.96 (br s, 4 H), 2.81 (t, J=5.4H), 2.63 (br s, 2 H), 2.49 (s, 2 H),1.87-1.82 (m, 2 H), 1.72-1.61 (m, 2 H). MS (ES) m/z: 435.23 (M+1)⁺(Exact mass: 434.23).

Example B19′ Synthesis of7-[4-(4-lsochroman-8-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-isochroman-8-yl-piperazine to give the title compound. ¹ H NMR (400MHz, CDCl₃) δ 9.14 (br s, 1 H), 7.72 (d, J=8.3 Hz, 1 H), 7.63 (d, J=9.2Hz, 1 H), 7.16 (t, J=7.8 Hz, 1 H), 6.94 (d, J=7.8 Hz, 1 H), 6.88 (d,J=7.3 Hz, 1 H), 6.60 (d, J=8.8 Hz, 1 H), 6.52 (d, J=9.2 Hz, 1 H), 4.78(s, 2 H), 4.39 (t, J=6.3 Hz, 2 H), 3.96 (t, J=5.9 Hz, 2 H), 2.91-2.86(m, 4 H), 2.61 (br s, 2 H), 2.50 (t, J=7.8 Hz, 2 H), 1.88-1.81 (m, 2 H),1.75-1.68 (m, 2 H). MS (ES) m/z: 435.23 (M+1)⁺(Exact mass: 434.23).

Example B20′ Synthesis of7-{4-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

In a manner similar to that of other examples above,1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazine hydrochloride(J. Med. Chem. 1988, 31, 1934-1940) was coupled by reductive aminationto 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehydefollowed by typical workup and purification to give the title compound.MS: APCl: M+1: 451.2 (Exact Mass: 450.23).

Example B21′ Synthesis of7-[4-(4-Quinolin-8-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using8-piperazin-1-yl-quinoline to give the title compound. MS: APCl: M+1:430.3(Exact mass: 429.22).

Example B22′ Synthesis of7-[4-(4-Quinolin-5-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using5-piperazin-1-yl-quinoline to give the title compound. MS: APCl: M+1:430.2 (Exact mass: 429.22).

Example B23′ Synthesis of7-[4-(4-Quinoxalin-5-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using5-piperazin-1-yl-quinoxaline to give the title compound. MS: APCl: M+1:431.2 (Exact mass: 430.21).

Example B24′ Synthesis of7-{4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using4-piperazin-1-yl-1H-indole to give the title compound. MS: APCl: M+1:418.2 (Exact mass: 417.22).

Example B25′ Synthesis of7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-benzo[b]thiophen-4-yl-piperazine to give the title compound. MS: APCl:M+1: 435.2 (Exact mass: 434.18).

Example B26′ Synthesis of7-[4-(4-Benzofuran-7-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-benzofuran-7-yl-piperazine to give the title compound. MS: APCl: M+1:419.2 (Exact mass: 418.20).

Example B27′ Synthesis of 7-{4-[4-(1-Acetyl-1,2,34-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

A first intermediate compound4-(1,2,3,4-Tetrahydro-quinolin-5-yl)-piperazine-1-carboxylic acidtert-butyl ester, was produced as follows: To a stirred solution ofcompound 4-quinolin-5-yl-piperazine-1-carboxylic acid tert-butyl ester(3.0 g, 9.58 mmol) in methanol (60 mL) cooled to −5° C., was addednickel chloride hexahydrate (2.28 g, 9.58 mmol) and sodium borohydride(1.45 g, 38.3 mmol). The resulting mixture was stirred at roomtemperature overnight and quenched with saturated ammonium chloridesolution. Ethyl acetate (100 mL) was added and the organic layer wasseparated. The aqueous layer was re-extracted with ethyl acetate (2×100mL). The combined organic extracts were washed with brine, dried(Na₂SO₄) and the solvent was removed in vacuo. The residue was purifiedby SiO₂ chromatography using hexanes-ethyl acetate (2:1) as eluent togive the first intermediate compound (1.82 g, 5%) as a solid. 1H NMR(400 MHz, CDCl₃): δ 6.95 (m, 1H), 6.38 (d, 1H), 6.25 (d, 1H), 3.58 (brs, 4H), 3.30 (t, 2H), 2.84 (br s, 4H), 2.72 (t, 2H), 1.88 (m, 2H), 1.45(s, 9H).

A second intermediate compound,4-(1-Acetyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazine-1-carboxylicacid tert-butyl ester, was produced as follows: To a stirred solution of4-(1,2,3,4-tetrahydro-quinolin-5-yl)-piperazine-1-carboxylic acidtert-butyl ester (1.38 g, 4.35 mmol) in dichloromethane (30 mL) at 0° C,was added triethylamine (0.79 g, 7.83 mmol) and acetic anhydride (0.67g, 6.53 mmol). The resulting mixture was stirred at room temperatureovernight and diluted with additional dichloromethane (50 mL). Water wasadded and the organic layer was separated. The aqueous layer wasre-extracted with dichloromethane. The combined organic extracts werewashed brine, dried (Na₂SO₄) and the solvent was removed in vacuo. Theresidue was purified by silica gel chromatography using hexanes-ethylacetate (1: 2) as eluent to give the second intermediate compound (1.50g, 97%) as a foam. ¹H NMR (400 MHz, CDCl₃): δ 7.20 (m, 1H), 6.83 (br,1H), 6.80 (d, 1H), 3.80 (t, 2H), 3.50 (br s, 4H), 2.85 (br s, 4H), 2.62(t, 2H), 2.25 (s, 3H), 1.90 (t, 2H), 1.50 (s, 9H).

A third intermediate compound,1-(5-Piperazin-1-yl-3,4-dihydro-2H-quinolin-1-yl)-ethanone, was producedas follows: To a stirred solution of4-(1-acetyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazine-1-carboxylicacid tert-butyl ester (0.90 g, 2.51 mmol) in dichloromethane (15 mL)cooled to 0° C, was added trifluoroacetic acid (2.86 g, 25.08 mmol). Theresulting mixture was stirred at room temperature overnight and thesolvent was removed in vacuo. The solid formed upon addition of diethylether was filtered to give the third intermediate compound (0.82 g,88%). ¹H NMR (400 MHz, DMSO-d6): δ 8.84 (br s, 1H), 7.20 (br s, 2H),6.82 (d, 2H), 3.64 (t, 2H), 3.24 (br s, 4H), 3.08 (br s, 4H), 2.64 (t,2H), 2.20 (s, 3H), 1.80 (t, 2H). MS ES: m/z 260.15 (M+H)⁺ (Exact mass:259.17).

The reductive amination procedure from Example B1′ was followed using1-(5-piperazin-1-yl-3,4-dihydro-2H-quinolin-1-yl)-ethanone to give thetitle compound. ¹H NMR (400 MHz, CDCl₃): δ 8.92 (s, 1H), 7.75 (d, 1H),7.65 (d, 1H), 7.18 (m, 1H), 6.90 (m, 2H), 6.60 (d, 1H), 6.50 (d, 1H),4.40 (t, 2H), 3.75 (t, 2H), 2.95 (br s, 4H), 2.65 (br s, 4H), 2.50 (t,2H), 2.20 (s, 3H), 1.90 (m, 4H), 1.70 (m, 2H). MS ES: m/z 476.2 (M+H)⁺(Exact mass: 475.26).

Example B28′ Synthesis of7-{4-[4-(1-Methyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-methyl-5-piperazin-1-yl-1,2,3,4-tetrahydro-quinoline to give the titlecompound. ¹H NMR (400MHz, CDCl₃): δ 9.75 (br s, 1H), 7.70 (d, 1H), 7.65(d, 1H) 7.05 (t, 1H), 6.62 (d, 1H), 6.58 (d, 1H), 6.42 (2H), 4.40 (t,2H), 3.22 (t, 2H), 2.95 (br s, 4H), 2.85 (s, 3H), 2.80-2.45 (m, 8H),1.95-1.65 (6H). MS ES: m/z 448.12 (M+H)⁺ (Exact mass: 447.26).

Example B29′ Synthesis of7-{4-[4-(1-Ethyl-1,2,3,4-tetrahydro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using1-ethyl-5-piperazin-1-yl-1 ,2,3,4-tetrahydro-quinoline to give the titlecompound. ¹H NMR (400 MHz, CDCl₃): δ 12.80 (br s, 1H), 7.70 (d, 1H),7.65 (d, 1H), 7.25 (m, 2H), 7.05 (br s, 1H) 6.62 (d, 1H), 6.59 (d, 1H),4.40 (m, 2H), 3.65 (m, 4 H), 3,45 (m, 4H), 3.25-3.00 (m, 8H), 2.80 (m,2H), 2.25-1.85 (m, 4H), 1.30 (t, 3H). MS ES: m/z 462.12 (M+H)⁺ (Exactmass: 461.28).

Example B30′ Synthesis of7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using2-methoxy-8-piperazin-1-yl-quinoline to give the title compound (0.73 g,92%). ¹H NMR (400 MHz, CDCl₃) δ 9.00 (br. s, 1H), 7.98 (d, 1H), 7.75 (d,1H), 7.62 (d, 1H), 7.38 (d, 1H), 7.30 (t, 1H), 7.10 (d, 1H), 6.90 (d,1H), 6.60 (d, 1H), 6.50 (d, 1H), 4.40 (t, 2H), 4.05 (s, 3H), 3.50 (br.s, 4H), 2.82 (m, 6H), 2.68 (t, 2H), 2.50 (dd, 2H), 1.82 (m, 2H), 1.78(m, 2H).

Example B31′ Synthesis of7-{4-[4-(2-Ethoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using2-ethoxy-8-piperazin-1-yl-quinoline to give the title compound. ¹H NMR(400MHz, CDCl₃) δ 9.06 (brs, 1H), 7.98 (d, 1H), 7.75 (d, 1H), 7.62 (d,1H), 7.38 (d, 1H), 7.30 (t, 1H), 7.1 0 (d, 1H), 6.90 (d, 1H), 6.65 (d,1H), 6.55 (d, 1H), 4.58 (t, 2H), 4.40 (t, 2H), 3.50 (brs, 4H), 2.82 (m,4H), 2.58 (t, 2H), 1.90 (m, 2H), 1.80 (m, 2H), 1.60 (t, 3H); MS (ES):m/z: 474.26 (M+H)⁺ (Exact mass: 473.24).

Example B32′ Synthesis of7-{4-[4-(2-Dimethylamino-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed usingdimethyl-(8-piperazin-1-yl-quinolin-2-yl)-amine to give the titlecompound (0.144 g; 51%). MS: APCl: M+1: 473.2 (Exact mass: 472.26).

Example B33′ Synthesis of7-{4-[4-(2-Methylamino-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed usingmethyl-(8-piperazin-1-yl-quinolin-2-yl)-amine to give the title compound(0.282 g; 70%). MS: APCl: M+1: 459.3 (Exact mass: 458.24).

Example B34′ Synthesis of7-{4-[4-(3-Fluoro-quinolin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using3-fluoro-5-piperazin-1-yl-quinoline to give the title compound (433 mg,66%). ¹H NMR (400 MHz, dmso-d₆) δ 12.00 (s, 1H), 8.90 (s, 1H), 8.05 (d,1H), 8.00 (d, 1H), 7.80 (d, 1H), 7.76 (d, 1H), 7.64 (t, 1H), 7.24 (d,1H), 6.62 (d, 1H), 6.38 (s, 1H), 4.40 (t, 2H), 3.05-2.90 (m, 4H),2.80-2.60 (m, 4H), 2.44 (t, 2H), 1.82-1.70 (m, 2H), 1.70-1.60 (m, 2H),MS ES+ 448.23 (M+1)⁺ (Exact mass: 447.21).

Example B35′ Synthesis of7-{4-[4-(3-Fluoro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using3-fluoro-8-piperazin-1-yl-quinoline to give the title compound (420 mg,66%). MS ES+ 448.16 (M+1)⁺ (Exact mass: 447.21).

Example B36′ Synthesis of7-{4-[4-(2-Oxo-1,2-dihydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

In a manner similar to that of other examples above,8-piperazin-1-yl-1H-quinolin-2-one hydrochloride (Chem. Pharm. Bull.1984, 32, 2100-2110) was coupled by reductive amination to4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followedby typical workup and purification to give the title compound. MS: APCl:M+1: 446.2 (Exact Mass: 445.21).

Example B37′ Synthesis of7-{4-[4-(2-Oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

In a manner similar to that of other examples above,8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride (Chem.Pharm. Bull. 1984, 32, 2100-2110) was coupled by reductive amination to4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followedby typical workup and purification to give the title compound. MS: APCl:M+1: 448.3 (Exact Mass: 447.23).

Example B38′ Synthesis of7-{4-[4-(1-Methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

In a manner similar to that of other examples above,1-methyl-8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloridewas coupled by reductive amination to4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followedby typical workup and purification to give the title compound. MS: APCl:M+1: 462.2 (Exact Mass: 461.24).

Example B39′ Synthesis of7-[4-(4-Benzo[1,2.5]oxadiazol-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using4-piperazin-1-yl-benzo[1,2,5]oxadiazole hydrochloride (Vogel, Martin;Karst, Uwe. (2001) DE 19936731) to give the title compound (0.161 g;45%). MS: APCl: M+1: 421.2 (Exact mass: 420.19).

Example B40′ Synthesis of7-[4-(4-Benzo[1.2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one

The reductive amination procedure from Example B1′ was followed using4-piperazin-1-yl-benzo[1,2,5]thiadiazole (Lowe, John A., Ill.; Nagel,Arthur A. (1989), U.S. Pat. No. 4,831,031) to give the title compound(0.336 g; 60%). MS: APCl: M+1: 439.2 (Exact mass: 438.17).

Example B41′ Synthesis of7-{4-[4-(2-Trifluoromethyl-3H-benzoimidazol-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one

To a suspension of4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.211 g,0.908 mmol, 1.29 eq) and4-piperazin-1-yl-2-trifluoromethyl-1H-benzoimidazole (0.190 g, 0.703mmol, 1 eq) in dichloroethane (5 mL) was added NaBH(OAc)₃ (0.558 g,2.631 mmol, 3.74 eq). The slurry was allowed to stir overnight at roomtemperature (18 h). The mixture was diluted with EtOAc and quenched withsaturated NaHCO₃. The organic phase was then washed with brine, driedover Na₂SO₄, filtered and evaporated in vacuo. Purification by silicagel chromatography (2% MeOH/CH₂Cl₂) followed by formation of the HCIsalt using 1N HCl in ether provided the title compound (0.230 g, 62%).MS: APCl: M+1: 487.1 (Exact Mass: 486.20).

Example C1′ Synthesis of4,4-Dimethyl-7-[4-(4-quinolin-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound 3-Methyl-but-3-enoic acid(6-amino-pyridin-2-yl)-amide, was produced as follows:2,5-Diaminopyridine (70 g, 0.641 mol) was dissolved in 2100 mL THF in a5 L 4-neck flask equipped with mechanical stirring, N₂ line and a 500 mLaddition funnel. Et₃N (447 mL, 5 eq.) was added to the reaction flask.3,3-Dimethylacryloyl chloride (76 g, 0.641 mol) was diluted with 700 mLTHF and this solution was added dropwise to the reaction flask. Themoderate exotherm observed was controlled with an ice/water bath tomaintain a temperature <15° C. After the addition was complete, thereaction was allowed to warm to room temperature and stirred under N₂for 1.5 h. The reaction mixture was concentrated and CH₂Cl₂ was added.The CH₂Cl₂ solution was washed with H₂0 and the aqueous layer was backextracted with CH₂Cl₂. The organic layers were combined and dried overNa₂SO₄, filtered and concentrated to an oil. The crude product waspurified by column chromatography using a gradient mobile phase of10%-30% EtOAc in hexanes. All fractions containing the desired productwere pooled and concentrated to an oil. NMR analysis of the productindicated the product was a 1:1 mixture of 2 isomers, the alpha betaunsaturated and the beta gamma unsaturated isomer resulting in firstintermediate compound (90.0 g, 0.47 mol, 73%). MS: APCl: M+1: 192.0(Exact Mass: 191.11).

A second intermediate compound,7-Amino-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one, wasproduced as follows: 3-Methyl-but-3-enoic acid(6-amino-pyridin-2-yl)-amide (49.2 g, 0.26 mol) was dissolved in 500 mLCH₂Cl₂ in a 1000 mL 3-neck flask equipped with mechanical stirring, a125 mL addition funnel and a thermal couple. While stirring, MeSO₃H (50mL, 0.78 mol) was added to the flask dropwise. The exotherm uponaddition was controlled to maintain a temperature <20° C. by anice/water bath. The mixture was allowed to stir for 15 minutes. AlCl₃(274 g, 2.08 mol) was suspended in 1500 mL CH₂Cl₂ in a 5 L 4-neck flaskequipped with mechanical stirring, 1000 mL addition funnel, N₂ line anda thermal couple. To this suspension, the amide solution was addeddropwise. The exotherm from the addition was again controlled tomaintain a temperature <20° C. with an ice/water bath. The reaction wasallowed to warm to room temperature and stir overnight. The reaction hadconsumed all the beta gamma unsaturated isomer and was deemed complete.The reaction mixture was slowly added to ice as an inverse quench. Thequenched mixture was brought to pH 8-10 with 2 N KOH. The saltsprecipitated out of solution and saturated the aqueous phase. Thesuspension was transferred to a separatory funnel and extracted twicewith 100:8:1 CH₂Cl₂:EtOH:NH₄OH. The organic layers were combined, driedover Na₂SO₄, filtered and concentrated to a crude solid. The solid wastriturated with EtOAc and filtered. The resulting solids were puresecond intermediate compound (22.4 g, 0.117 mol, 46%). MS: APCI: M+1:192.2 (Exact Mass: 191.11).

A third intermediate compound,7-Fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one, wasproduced as follows: HF-pyridine (100 mL) was cooled to −42° C. in a1000 mL HDPE bottle using an CH₃CN dry ice bath. While stirringvigorously, 7-amino-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one(24.6 g, 0.129 mol) was added portionwise to control the exotherm. Afterthe addition, NaNO₂ (8.9 g, 0.1291 mol) was added portionwise.Significant exotherms were observed for both additions. The reactionmixture was then allowed to warm to 0° C. and stir for 2 h. The reactionmixture was quenched into a 4 L HDPE bottle full of ice. The aqueousslurry was then neutralized using 2 N KOH. The resulting aqueoussolution was extracted 3 times with CH₂Cl₂. The organic layers weredried over Na₂SO₄, filtered and concentrated to dryness. Excess pyridinewas azeotroped with heptane. The product was dried under vacuum (2 mmHg) for 3 h. The third intermediate compound was isolated as a whitepowder (23.06 g, 0.119 mol, 92%). MS: APCl: M+1: 195.1 (Exact Mass:194.09).

A fourth intermediate compound,7-(4-Hydroxy-butoxy)-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows: The7-fluoro-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one (5.09 g,26.2 mmol) and butane-1,4-diol (11.81 g, 131.0 mmol) were combined in adried 2-necked flask under N₂. NMP (50 mL) was added and the solutionwas heated in an oil bath to 70° C. overnight. The reaction was cooledto room temperature and poured into ice water. The solid that formed wascollected and triturated in acetonitrile to give the fourth intermediatecompound as a tan powder (1.72 g). The mother liquor was extracted withCH₂Cl₂, dried over Na₂SO₄, filtered and purified by MPLC (gradient of100% CH₂Cl₂ to 100% ethyl acetate). The compound was isolated as amixture with diol byproducts. The fourth intermediate compound wasformed as clear crystals (1.09 g) after recrystallization inacetonitrile and another 340 mg was obtained from a secondrecrystallization. The products were combined to give a total of 3.15 gof the fourth intermediate compound (11.9 mmol, 45.5%). MS: APCl: M+1:265.1 (Exact Mass: 264.15).

A fifth intermediate compound,4-(5,5-Dimethyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde,was produced as follows:7-(4-Hydroxy-butoxy)-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one(1.72 g, 6.51 mmol) was dissolved in ethyl acetate (50 mL, 0.14 Msolution) and IBX (13 g, 46.4 mmol) was added. The suspension wasimmersed in an oil bath set at 80° C. and stirred vigorously with acondenser. After 1.5 h, the reaction mixture was cooled to roomtemperature and filtered. The filtrate was concentrated to give thefifth intermediate compound as a tan solid (1.62 g, 6.18 mmol, 95%). MS:APCl: M+1: 263.1 (Exact Mass: 262.13).

The naphthyridinones of Examples C1′-C6′ were synthesized in acombinatorial library format by reductive amination of the appropriatepiperazine starting materials with4-(5,5-dimethyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydeusing the following general procedure.

The aldehyde (0.3 mmol) and the piperazine (60.306 mmol) were combinedin methylene chloride and stirred in a vial over sieves for 10 min.Sodium triacetoxyborohydride (0.42 mmol) was added and the reaction wasstirred overnight. The reaction was quenched by slowly adding water andthen the mixture was filtered. The residue was partitioned betweenCH₂Cl₂ and water and the organic layer was concentrated. Purification byliquid chromatography (MPLC, gradient of 100% CH₂Cl₂ to 100% of a 10%MeOH in CH₂Cl₂ solution) gave the title compound. The final productswere made into hydrochloride salts by treatment with a solution ofsaturated HCl in MeOH.

The title compound was isolated as a foam (207 mg, 0.451 mmol, 75.1%).MS: APCl: M+1: 460.2 (Exact Mass: 459.26).

Example C2′ Synthesis of7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was isolated as a white solid (91 mg, 0.195 mmol,39.2%). MS: APCl: M+1: 467.2 (Exact Mass: 466.26).

Example C3′ Synthesis of4,4-Dimethyl-7-{4-[4-(2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was isolated as the hydrochloride salt (101 mg, 0.196mmol, 25.7%). MS: APCl: M+1: 478.3 (Exact Mass: 477.27).

Example C4′ Synthesis of4,4-Dimethyl-7-{4-[4-(2-oxo-1,2-dihydro-quinolin-8-yl)-pirerazin-1-yl]-butoxyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was isolated as the hydrochloride salt (140 mg, 0.273mmol, 35.8%). MS: APCl: M+1: 476.2 (Exact Mass: 475.26).

Example C5′ Synthesis of7-[4-(4-Benzofuran-7-yl-piperazin-1-yl)-butoxy]-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was isolated as the hydrochloride salt (105 mg, 0.216mmol, 28.4%). MS: APCl: M+1: 449.3 (Exact Mass: 448.25).

Example C6′ Synthesis of7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-4,4-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was isolated as a white solid (221 mg, 0.476 mmol,56.7%). MS: APCl: M+1: 465.2 (Exact Mass: 464.28).

Example D1′ Synthesis of6-Fluoro-7-[4-(4-quinolin-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

A first intermediate compound6-(4-Benzyloxy-butoxy)-2-chloro-5-fluoro-nicotinonitrile, was producedas follows: To a solution of 4-benzyloxy-1-butanol (19.44 g, 108 mmol)in THF (200 mL) cooled to −40° C. was added 1M KO^(t)Bu in THF (108 mL,108 mmol). The mixture was stirred for 5 min at −10° C. and then addedto a solution of 2,6-dichloro-5-fluoro-nicotinonitrile (20.0 g, 105mmol) in THF (300 mL) cooled to −70° C. over 25 min. The mixture turnedbrownish yellow with some cloudiness. The reaction was allowed to warmto room temperature over 2 h. The THF was evaporated and the residue wasdiluted with Et₂O. The mixture was washed with water, brine, 1N citricacid, water and brine, dried over Na₂SO₄ and concentrated to an oil. Theoil was dissolved in Et2O/hexanes and cooled in the refrigeratorovernight. A crystalline solid formed which was collected by filtration,washed with hexanes and dried to give the first intermediate compound asa white solid (17.0 g). The filtrate was concentrated and purified bysilica gel chromatography (Biotage 40 L, 0-6% EtOAc/Hexanes) to giveadditional first intermediate compound as a white solid (total of 26.9g, 80.4 mmol, 77%). MS: APCl: M+1: 335.1 (Exact Mass: 334.09).

A second intermediate compound,2-Azido-6-(4-benzyloxy-butoxy)-5-fluoro-nicotinonitrile, was produced asfollows: To a solution of6-(4-benzyloxy-butoxy)-2-chloro-5-fluoro-nicotinonitrile (20.0 g, 60.0mmol) in DMF (40 mL) was added sodium azide (4.27 g, 65.7 mmol) and themixture was heated at 70° C. overnight. The mixture was poured into Et₂Oand washed with water and brine. The Et₂O solution was passed through asilica gel Biotage 12M column, dried over MgSO₄ and charcoal, andconcentrated to give an oil (19.67 g). Recrystallization from Et₂O/MeOHgave the second intermediate compound as a solid (17.24 g, 50.5 mmol,84%). MS: APCl: M+1: (Exact Mass: 341.13).

A third intermediate compound,2-Amino-6-(4-benzyloxy-butoxy)-5-fluoro-nicotinonitrile, was produced asfollows: To a solution of2-azido-6-(4-benzyloxy-butoxy)-5-fluoro-nicotinonitrile (17.2 g, 50.4mmol) in MeOH (450 mL) was added hexamethyldisilthiane (19.0 g, 106.5mmol). The reaction gives off a gas and a precipitate forms after 15min. The reaction was stirred overnight at room temperature and thenfiltered to remove the precipitated sulfur. The mixture was concentratedand then redissolved in Et₂O. The mixture was filtered again to removeadditional precipitated sulfur. The filtrate was concentrated andrecrystallized from MeOH/hexanes. The solid was collected by filtration,washed with hexane/MeOH and dried to give the third intermediatecompound (13.74 g, 43.57 mmol, 86%). MS: APCl: M+1: 316.4 (Exact Mass:315.14).

A fourth intermediate compound,2-Amino-6-(4-benzyloxy-butoxy)-5-fluoro-pyridine-3-carbaldehyde, wasproduced as follows: To a solution of2-amino-6-(4-benzyloxy-butoxy)-5-fluoro-nicotinonitrile (7.25 g, 23.0mmol) in THF (40 mL) cooled to 0° C. is added DIBALH (1M in THF, 69 mL,69 mmol). The reaction was complete after 5 min. Chilled 2N HCl wasadded very slowly (strong exotherm) to quench the reaction. The mixtureforms a red gelatinous material. Et₂O was added and the layers wereseparated. The organic layer was washed with brine and saturated NaHCO₃and then filtered through Celite. There may still have been somealuminum complexed product so the organic solution was washed again with2N HCl, brine, saturated NaHCO₃ and brine, dried over MgSO₄ andconcentrated to give the crude fourth intermediate compound as an orangeoil (5.23 g, 16.4 mmol, 71%). MS: APCl: M+1: 319.2 (Exact Mass: 318.14).

A fifth intermediate compound,3-[2-Amino-6-(4-benzyloxy-butoxy)-5-fluoro-pyridin-3-yl]-acrylic acidethyl ester, was produced as follows: To a solution of2-amino-6-(4-benzyloxy-butoxy)-5-fluoro-pyridine-3-carbaldehyde (5.23 g,16.4 mmol, crude from previous reaction) in THF (50 mL) was added(carbethoxymethylene)triphenylphosphorane (5.72 g. 16.43 mmol) and thesolution was heated at 67° C. overnight. The reaction was concentratedand the residue was purified by liquid chromatography (Biotage 65M,0-10% EtOAc/CH₂Cl₂) to give the fifth intermediate compound as a yellowsolid (73%). MS: APCl: M+1: 389.4 (Exact Mass: 388.18).

A sixth intermediate compound,7-(4-Benzyloxy-butoxy)-6-fluoro-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows:3-[2-Amino-6-(4-benzyloxy-butoxy)-5-fluoro-pyridin-3-yl]-acrylic acidethyl ester (7.18 g, 18.5 mmol) was hydrogenated under an atmosphere ofH₂ (4300 psi) using Ra—Ni (2 g) in MeOH (100 mL). The reaction wasfiltered and concentrated. MS indicated the double bond had been reducedand some of the material cyclized. The material was suspended in^(i)PrOH and p-toluenesulfonic acid hydrate (0.41 g) was added. Themixture was heated at 80° C. for 30 min. Saturated NaHCO₃ was added andthe mixture was concentrated. The residue was partitioned between Et₂Oand water. The organic layer was washed with saturated NaHCO₃ and brine,dried over MgSO₄ and concentrated to give a yellow oil which solidified.Recrystallization from Et₂O/hexane afforded the sixth intermediatecompound as a pale yellow solid. MS: APCl: M+1: 345.1 (Exact Mass:344.15).

A seventh intermediate compound,6-Fluoro-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one,was produced as follows:7-(4-Benzyloxy-butoxy)-6-fluoro-3,4-dihydro-1H-[1,8]naphthyridin-2-one(4.79 g, 13.9 mmol) was hydrogenated under an atmosphere of H₂ using 20%Pd/C (1.0 g) in EtOH (100 mL). The reaction was filtered andconcentrated to give a slurry. Et₂O was added and the solids werefiltered. The filtrate was concentrated and the process was repeated togive the seventh intermediate compound as a solid (3.2 g, 13.0 mmol,91%). MS: APCl: M+1: 255.1 (Exact Mass: 254.11).

A eighth intermediate compound,4-(3-Fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde,was produced as follows: To a solution of oxalyl chloride (1.78 g, 14.0mmol) in CH₂Cl₂ (25 mL) cooled to −70° C. was added a solution of DMSO(2.15 g, 27.6 mmol) in CH₂Cl₂ (1.5 mL) over 4 min. The mixture wasstirred for 5 min and a solution of6-fluoro-7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,8]naphthyridin-2-one(3.1 g, 12.0 mmol) in DMSO (4.5 mL) and CH₂Cl₂ (44 mL) cooled to −50° C.was added over 5 min. The mixture was stirred for 10 min at −70° C. andit solidified. The reaction was warmed to −30° C. and triethylamine (8.9mL, 63.8 mmol) was added resulting in a stirable suspension. Thereaction was warmed to room temperature over 30 min. The mixture wasadded to water and the layers were separated. The organic layer waswashed with water and dilute brine, dried over MgSO₄ and concentrated togive an oil. The residue was partitioned between Et₂O and aqueous citricacid (pH 4.5). The organic layer was washed with dilute aqueous NaHCO₃and brine, dried over MgSO₄ and concentrated to give the eighthintermediate compound as a yellow oil (1.89 g) which was used directlyin the next reaction. MS: APCl: M+1: 253.2 (Exact Mass: 252.09).

The title compound was prepared by reductive amination of4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydewith 8-piperazin-1-yl-quinoline using a procedure similar to ExampleA1′. MS: APCl: M+1: 450.2 (Exact Mass: 449.22).

Example D2′ Synthesis of6-Fluoro-7-[4-(4-isoquinolin-5-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one

The title compound was prepared by reductive amination of4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehydewith 5-piperazin-1-yl-isoquinoline using a procedure similar to ExampleA2′. MS: APCl: M+1: 450.2 (Exact Mass: 449.22).

Example E1′ Synthesis of7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-1H-pyrido[2,3-d]pyrimidin-2-one

A first intermediate compound2-Amino-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridine-3-carbaldehyde,was produced as follows: A mixture ofN-{3-formyl-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-2-yl}-2,2-dimethyl-propionamide(9.8 g, 25.9 mmol), 2 N KOH (35 mL) and EtOH (40 mL) was heated at 80°C. for 2 h. Ethanol was removed under reduced pressure and the residuewas extracted with EtOAc (3×100 mL). The combined organic phases werewashed with H₂O (40 mL) and brine (40 mL), dried over Na₂SO₄, andconcentrated to give the first intermediate compound as an oil which wasused in the next step without further purification. ¹H NMR (400 MHz,CDCl3): δ 9.70 (s,1H), 7.62 (d, 1H), 6.17 (d, 1H), 4.60 (m, 1H), 4.40(m, 2H), 3.90 (m, 2H), 3.50 (m, 2H), 2.00-1.50 (m, 10H).

A second intermediate compound,7-[4-(Tetrahydro-pyran-2-yloxy)-butoxy]-1H-pyrido[2,3-d]pyrimidin-2-one,was produced as follows: To a solution of2-amino-6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridine-3-carbaldehydeobtained in the last step in CH₂Cl₂ (50 mL) was added trichloroacetylisocyanate (5.85 g, 31.08 mmol) dropwise. After the addition was over,the mixture was stirred at room temperature for 1 h. To this mixture,MeOH (50 mL) and 1 N NaOH (40 mL) were added successively. The mixturethus obtained was kept stirring at room temperature for another 1 h. Thesolvent was then removed under reduced pressure and the residue wasextracted with CH₂Cl₂ (3×100 mL). The combined organic phases werewashed with brine, dried and concentrated. The residue was crystallizedfrom ether to give the second intermediate compound (6.6 g, 79% in twosteps) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.00 (s,1H), 8.00 (d, 1H), 6.60 (d, 1H), 4.60 (m, 1H), 4.40 (m, 2H), 3.70 (m,2H), 3.40 (m, 2H), 1.90-1.30 (m, 10H).

A third intermediate compound,7-(4-Hydroxy-butoxy)-1H-pyrido[2,3-d]pyrimidin-2-one, was produced asfollows: A mixture of7-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-1H-pyrido[2,3-d]pyrimidin-2-one(4.9 g, 15 mmol), MeOH (30 mL), THF (15 mL) and 3 N HCl (7.5 mL) wasstirred at room temperature for 1 h. The mixture was concentrated underreduced pressure. The residue was dissolved in H₂O (30 mL) andneutralized carefully with saturated NaHCO₃. The mixture was extractedwith THF (5×100 mL). The combined organic phases were washed with brine,dried and concentrated to give the third intermediate compound (3.3 g,90%) which was used in the next step without further purification. ¹HNMR (400 MHz, DMSO-d₆): δ 9.03(s, 1H), 8.17 (d, 1H), 6.67 (d, 1H), 4.50(m, 1H), 4.40 (m, 2H), 3.50 (m, 3H), 1.80 (m, 2H), 1.55 (m, 2H).

A fourth intermediate compound,4-(2-Oxo-1,2-dihydro-pyrido[2,3-d]pyrimidin-7-yloxy)-butyraldehyde, wasproduced as follows: A mixture of7-(4-hydroxy-butoxy)-1H-pyrido[2,3-d]pyrimidin-2-one (0.512 g, 2.18mmol) and IBX (1.9 g, 6.6 mmol) in CH₃CN (40 mL) was heated at 87° C.for 7 h. It was cooled to RT, diluted with EtOAc (80 mL) and filtered.The pad was washed thoroughly with EtOAc. The combined filtrate wasconcentrated to give the fourth intermediate compound as a solid whichwas contaminated with some byproduct from the reaction. This solid wasused in the next step without further purification. ¹H NMR (400 MHz,DMSO-d₆): δ 12.18 (s, 1H), 9.77 (s, 1H), 8.20 (d, 1H), 6.70 (d, 1H),4.40 (m, 2H), 2.70 (m, 2H), 2.00 (m, 2H).

To a mixture of4-(2-oxo-1,2-dihydro-pyrido[2,3-d]pyrimidin-7-yloxy)-butyraldehydeobtained in the last step, 1-chroman-8-yl-piperazine hydrochloride(0.634 g, 2.18 mmol), Et₃N (0.73 mL, 5.23 mmol) in1-methyl-2-pyrrolidinone (20 mL) was added NaBH(OAc)₃ (0.514 g, 2.62mmol) in portions over 20 min. The mixture was stirred overnight. Afterquenching with H₂O (50 mL), the reaction mixture was extracted withCH₂Cl₂ (3×100 mL). The combined organic phases were washed with brine(100 mL), dried and concentrated. The residue was purified bychromatography on silica gel to give a gum (520 mg). To a solution ofthis gum (200 mg) in THF (2 mL) was added 1 N HCl (0.43 mL) in Et₂O. Themixture was stirred at room temperature for 30 min and filtered. Thesolid was washed with Et₂O and dried under vacuum to give the titlecompound (190 mg) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 12.30(s, 1H), 9.20 (s, 1H), 8.20 (d, 1H), 7.80 (m, 4H), 4.45 (m, 2H), 4.20(m, 2H), 3.60 (m, 4H), 3.20 (m, 2H), 3.00 (m, 2H), 2.00-1.70 (m, 6H).

Example E2′ Synthesis of7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

To a solution of7-[4-(4-chroman-8-yl-piperazin-1-yl)-butoxy]-1H-pyrido[2,3-d]pyrimidin-2-one(320 mg) in THF (6 mL) and MeOH (2 mL) was added NaBH₄ (54 mg) inportions. After the addition was over, the mixture was kept stirringovernight. The reaction was quenched with H₂O. The mixture was extractedwith CH₂Cl₂ (3×50 mL). The combined organic phases were dried overNa₂SO₄ and concentrated. The residue was purified by chromatography onsilica gel to give a semi-solid which was converted to its HCl salt bytreating with 1 equivalent of 1 N HCl in a mixed solvent of THF and Et₂Oto give the title compound (147 mg) as a white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 9.20 (s, 1H), 7.40 (d, 1H), 6.98 (s, 1H), 7.70 (m, 3H), 6.25(d, 1H), 4.30-4.06 (m, 6H), 3.60-3.30 (m, 4H), 3.15 (m, 4H), 3.00-2.70(, 4H), 2.00-1.60 (m, 6H).

Example E3′ Synthesis of7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

To a mixture of4-(2-oxo-1,2-dihydro-pyrido[2,3-d]pyrimidin-7-yloxy)-butyraldehyde,1-(2,3-dihydro-benzofuran-7-yl)-piperazine hydrochloride (0.76 g, 2.58mmol), Et₃N (2.15 mL, 15.5 mmol) in 1-methyl-2-pyrrolidinone (20 mL) wasadded NaBH(OAc)₃ (0.76 g, 3.61 mmol) in portions over 20 min. After theaddition was over, the mixture was left stirring overnight. Afterquenching with H₂0 (50 mL), the reaction mixture was extracted withCH₂Cl₂ (3×100 mL). The combined organic layer was washed with brine (100mL), dried and concentrated. The residue was purified by chromatographyon silica gel to give a gum (290 mg). To a solution of this gum in THF(6 mL) and MeOH (2 mL) was added NaBH₄ (63 mg) in portions. After theaddition was over, the mixture was kept stirring ovemight. The reactionwas quenched with H₂O. The mixture was extracted with CH₂Cl₂ (3×50 mL).The combined organic phases were dried over Na₂SO₄ and concentrated. Theresidue was purified by chromatography on silica gel to give asemi-solid which was converted to the HCl salt by treating with 1equivalent of 1 M HCl in a mixed solvent of THF and Et₂O to give thetitle compound (147 mg) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.20 (s, 1H), 7.40 (d, 1H), 7.00 (s, 1H), 6.95 (d, 1H), 6.80 (m, 1H),6.70 (d, 1H), 6.30 (d, 1H), 4.50 (t, 2H), 4.20 (m, 4H), 3.80-3.40 (m,4H), 3.20-2.90 (m, 8H), 1.90-1.60 (m, 4H).

Example E4′ Synthesis of7-{4-[4-(3,4-Dihydro-2H-benzol[b][1,4]dioxepin-6-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one

The procedure from Example E3′ was followed using1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazine to give thetitle compound. ¹H NMR (400 MHz, DMSO-d₆): δ 9.25 (s, 1H), 7.40 (d, 1H),6.90 (s, 1H), 6.80 (m, 1H), 6.60 (m, 2H), 6.25 (d, 1H), 4.30-4.00 (m,8H), 3.60-3.40 (4H), 3.20-3.00 (m, 6H), 2.10 (m, 2H), 1.90-1.60 (m, 4H).

Example F1′ Synthesis of6-{4-[4-(2-Methyl-quinolin-8-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one

A first intermediate compound 6-Amino-4H-pyrido[3,2-b][1,4]oxazin-3-one,was produced as follows: A mixture of6-nitro-4H-pyrido[3,2-b][1,4]oxazin-3-one (34.23 g, 0.1755 mol), 20%Pd-C (3.0 g, 50% H₂O) and DMF (1 L) was hydrogentated at 20 psi H₂pressure. After 2 h, uptake of H₂ ceased with 141 psi of H₂ beingabsorbed. The reaction mixture was filtered through a pad of Celite®,washing with DMF (500 mL). The filtrate was diluted with cold H₂O (2 L)to give a solid. The solid was collected, washed with H₂O, slurried inEtOH (150 mL), collected, washed with heptane and dried to give thefirst intermediate compound (23.60 g, 81%) as a gray-tan solid.

A second intermediate compound,6-Fluoro-4H-pyrido[3,2-b][1,4]oxazin-3-one, was produced as follows: A 1gallon Nalgene jar (with openings in the top for a N₂ inlet and additionof solids) was cooled in an ice/salt bath and hydrogen fluoride-pyridine(500 g) was added. With magnetic stirring and under a stream of N₂,6-amino-4H-pyrido[3,2-b][1,4]oxazin-3-one (88.48 g, 0.5362 mol, 1.0equiv) was added slowly portion-wise. When addition was complete, thered-brown mixture was stirred for 0.25 h to ensure complete solution.Sodium nitrite (44.40 g, 0.6435 mol, 1.2 equiv) was added cautiouslyportion-wise over 0.5 hr. Each addition was exothermic and accompaniedby the evolution of HF and N₂. When addition was complete the reactionmixture was stirred in the ice/salt bath for 1 h. The reaction wasquenched by the slow, careful addition of ice-cold H₂O (2 L). Theresulting solid was collected, washed with H₂O, resuspended in H₂O (3×1L), collected, washed with H₂O and dried on the filter for 1 h. Thesolid was washed with heptane and dried under a N₂ stream for 2 h. Finaldrying in a vacuum oven for 24 h at ˜40° C. gave the second intermediatecompound (69.03 g, 76%) as an orange-brown solid. Mp 179.9-181.2°.

A third intermediate compound,6-(4-Benzyloxy-butoxy)-4H-pyrido[3,2-b][1,4]oxazin-3-one, was producedas follows: A solution of 4-benzyloxy-butan-1-ol l (34.31 g, 33.37 mL,190.3 mmol) and potassium t-butoxide (1M solution; 181 mL) in THF (60mL) was prepared and stirred at room temperature for 20 min. Asuspension of 6-fluoro4H-pyrido[3,2-b][1,4]oxazin-3-one (8 g, 48 mmol)in THF (100 mL) was prepared, and the alcohol/base solution was added tothis solution via canula. The reaction was heated at reflux for 25hours. The reaction was quenched with saturated NH₄Cl and water. Thesolution was brought to a pH of 8 and extracted with ethyl acetate. Theorganic layer was washed with brine and concentrated to give a solid.Purification by SiO₂ chromatography (0-70% EtOAc/hexanes) gave the thirdintermediate compound as a white solid (6.6 g, 42%). MS: APCl: M+1:329.2 (Exact Mass: 328.14).

A fourth intermediate compound,6-(4-Hydroxy-butoxy)-4H-pyrido[3,2-b][1,4]oxazin-3-one, was produced asfollows: To a solution of6-(4-benzyloxy-butoxy)-4H-pyrido[3,2-b][1,4]oxazin-3-one (6.4 g, 19mmol) in MeOH/THF (100 mL) was added 20% Pd/C (1.5 g) and the mixturewas hydrogenated for 12 h. The reaction was filtered, concentrated andpurified by liquid chromatography (0-10% MeOH/CH₂Cl₂) to give the fourthintermediate compound as a white solid (4.3 g, 18 mmol, 93%). MS: APCl:M+1: 239.1 (Exact Mass: 238.10).

A fifth intermediate compound,4-(3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yloxy)-butyraldehyde,was produced as follows: To a suspension of6-(4-hydroxy-butoxy)-4H-pyrido[3,2-b][1,4]oxazin-3-one (4.3 g, 18.02mmol) in dichloroethane (30 mL) was added IBX (15 g, 54 mmol). Thismixture was heated at 80° C. for 5 hours. The reaction was cooled andstirred, and then filtered. The filter cake was washed with CH₂Cl₂ untilthe product was removed. The filtrate was concentrated to give a redoil, which was purified by SiO₂ chromatography (0-7% MeOH/CH₂Cl₂) togive the fifth intermediate compound as a red oil (3.90 g, 16.5 mmol,92%). MS: APCl: M+1: 237.1 (Exact Mass: 236.08).

A reductive amination procedure similar to Example A1′ was followedusing 2-methyl-8-piperazin-1-yl-quinoline to give the title compound(0.19 g, 51%). MS: APCl: M+1: 448.3 (Exact Mass: 447.23).

Example F2′ Synthesis of6-[4-(4-Quinolin-8-yl-piperazin-1-yl)-butoxy]-4H-pyrido[3.2-b][1,4]oxazin-3-one

A reductive amination procedure similar to Example A1′ was followedusing 8-piperazin-1-yl-quinoline to give the title compound (0.18 g,64%). MS: APCl: M+1: 434.3 (Exact Mass: 433.21).

Example F3′ Synthesis of6-{4-[4-(2-Oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one

A reductive amination procedure similar to Example A1′ was followedusing 8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one to give the titlecompound (0.20 g, 66%). MS: APCl: M+1: 452.3 (Exact Mass: 451.22).

Example F4′ Synthesis of6-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-4H-pyrido[3.2-b][1,4]oxazin-3-one

A reductive amination procedure similar to Example A1′ was followedusing 1-chroman-8-yl-piperazine to give the title compound (0.29 g,79%). MS: APCl: M+1: 439.3 (Exact Mass: 438.23).

Example F5′ Synthesis of6-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one

A reductive amination procedure similar to Example A1′ was followedusing 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine to give the titlecompound (0.22 g, 67%). MS: APCl: M+1: 441.1 (Exact Mass: 440.21).

Example G1′ Synthesis of2-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2.3-d]pyrimidin-7-one

A first intermediate compound2-Methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one, was produced asfollows: To a suspension of2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (5.0 g, 25.9 mmol) inCH₂Cl₂ (100 mL), CHCl₃ (50 mL) and MeOH (10 mL, the starting materialstill did not dissolve) was added the oxaziridine (8.11 g, 31.05 mmol,1.2 equiv) as a solid. The reaction became homogenous after 3 h and wasstirred overnight at RT. The reaction was concentrated and CH₂Cl₂/MeOHwas added to dissolve the residue. Much of the solid did not dissolve sothe mixture was filtered to give an off-white solid which was the firstintermediate compound (2.31 g, 11.04 mmol, 43%). MS: APCl: M+1: 210.1(Exact Mass: 209.03).

A second intermediate compound,2-[4-(Tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one,was produced as follows: To a solution of4-(tetrahydro-pyran-2-yloxy)-1-butanol (4.45 g, 25.3 mmol, 2.5 equiv) inTHF (20 mL) cooled to 0° C. was added 1M KOtBu in THF (25 mL, 25 mmol).The solution was stirred at 0° C. for 20 min and then added to asuspension of 2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (2.12 g,10.13 mmol) in DMF (30 mL) at RT. The reaction became homogenous and wasstirred at room temperature for 1 h. Saturated NH4Cl and H2O were addedto quench the reaction. The mixture was extracted with EtOAc. Theorganic layer was washed with H2O and brine, dried over Na2SO4 andconcentrated. Purification by liquid chromatography (70% EtOAc/Hexanesto 100% EtOAc) gave the second intermediate compound as a white solid(1.95 g, 6.11 mmol, 60%). MS: APCl: M+1: 320.2 (Exact Mass: 319.15).

A third intermediate compound,2-(4-Hydroxy-butoxy)-8H-pyrido[2,3-d]pyrimidin-7-one, was produced asfollows: To a suspension of2-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one(1.95 g, 6.11 mmol) in EtOH (30 mL) and CH2Cl2 (2 mL, added to helpdissolve the starting material) was added PPTS (151 mg, 0.6 mmol). Thesolution was stirred overnight at room temperature and then heated at60° C. for 5 h. The reaction was concentrated to give a white solid.Purification by liquid chromatography (6% MeOH/CH2Cl2) gave the thirdintermediate compound as a white solid (1.22 g, 5.19 mmol, 85%). MS:APCl: M+1: 236.1 (Exact Mass: 235.10).

A fourth intermediate compound,4-(7-Oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde, wasproduced as follows: To a solution of2-(4-hydroxy-butoxy)-8H-pyrido[2,3-d]pyrimidin-7-one (251 mg, 1.07 mmol)in DMSO (3 mL) was added a solution of IBX (597 mg, 2.13 mmol) in DMSO(7 mL, 0.3 M). The reaction was stirred at room temperature for 90 min,cooled to 0° C. and quenched with 5% NaHCO3. The mixture was extractedwith CH2Cl2 (4×). The organic layer was washed with 5% NaHCO3 and brine,dried over Na2SO4 and concentrated to give the fourth intermediatecompound as a white solid (171 mg, 0.733 mmol, 69%). MS: APCl: M+1:234.1 (Exact Mass: 233.08).

The pyrimidines of Examples G1′-G9′ were synthesized in a combinatoriallibrary format by reductive amination of the appropriate piperazinestarting materials with4-(7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde usingthe procedure outlined in Example C1′.

The title compound was isolated as white solid (292 mg, 0.637 mmol,74.3%). MS: APCl: M+1: 438.1 (Exact Mass: 437.21).

Example G2′ Synthesis of2-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as a white solid (258 mg, 0.564 mmol,65.8%). MS: APCl: M+1: 436.1 (Exact Mass: 435.23).

Example G3′ Synthesis of2-[4-(4-Quinolin-8-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as a yellow solid (225 mg, 0.522 mmol,61%). MS: APCl: M+1: 431.1 (Exact Mass: 430.21).

Example G4′ Synthesis of2-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2.3-d]pyrimidin-7-one

The title compound was isolated as a white solid (118 mg, 0.280 mmol,32.7%). MS: APCl: M+1: 422.1 (Exact Mass: 421.21).

Example G5′ Synthesis of2-{4-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as a white solid (117 mg, 0.259 mmol,30.2%). MS: APCl: M+1: 452.3 (Exact Mass: 451.22).

Example G6′ Synthesis of2-{4-[4-(2,2-Dimethyl-chroman-8-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as a white solid (202 mg, 0.435 mmol,50.8%). MS: APCl: M+1: 464.3 (Exact Mass: 463.26).

Example G7′ Synthesis of2-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as a white foam (249 mg, 0.541 mmol,63.2%). MS: APCl: M+1: 460.2 (Exact Mass: 459.17).

Example G8′ Synthesis of2-{4-[4-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as an off white foam (188 mg, 0.418mmol, 48.8%). MS: APCl: M+1: 450.1 (Exact Mass: 449.24).

Example G9′ Synthesis of2-{4-[4-(2-Methyl-quinolin-8-yl)-piperazin-1-yl]-butoxy}-8H-yvrido[2,3-d]pyrimidin-7-one

The title compound was isolated as tan crystals (93 mg, 0.209 mmol,24.4%). MS: APCl: M+1: 445.1 (Exact Mass: 444.23).

Example G10′ Synthesis of2-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one

A first intermediate compound2-Methanesulfonyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, was producedas follows: A solution of4-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (24 g, 0.1158mol, U.S. Pat No. 6,498,163) in a mixture of CH₂Cl₂ (1.9 L) and methanol(300 mL) is treated with m-chloroperbenzoic acid (103 9, 60%, 0.345 mol)in portions at room temperature. The mixture is stirred for 24 h, cooledto ˜5° C. and quenched with saturated sodium bicarbonate solution. Thesolids are filtered, washed thoroughly with water followed by ether anddried in vacuum to give the first intermediate compound as a solid (10g, 0.042 mol, 36%). MS: APCl: M+1: 240.0 (Exact Mass: 239.04).

A second intermediate compound,4-Methyl-2-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one,was produced as follows: To a ice bath cooled solution of4-(tetrahydro-pyran-2-yloxy)-butan-1-ol (27.3 g, 0.1567 mol) in dry THF(125 mL) is added drop wise a solution of KOtBu (1M, 155 mL, 0.155 mol)in THF within 15 min. The mixture is then stirred at 0° C. for 2 h. Tothis mixture is added a suspension of2-methanesulfonyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (15 g, 0.0627mol) in DMF (225 mL) at room temperature within 15 min. The orange redcolored reaction mixture is stirred at room temperature for 1.5 h,cooled and quenched with saturated NH₄Cl solution (150 mL) and water (2L). The mixture is extracted with ethyl acetate (2×0.75 L) and theorganic layer is washed with brine (300 mL), dried over anhydrous sodiumsulfate, filtered through a small bed of silica gel eluting with 5%methanol in ethyl acetate (750 mL) and concentrated. The residue is thentriturated with hexane, filtered and dried to give the secondintermediate compound as a white solid (16.5 g, 0.0495 mol 78%). MS:APCl: M+1: 334.0 (Exact Mass: 333.17).

A third intermediate compound,2-(4-Hydroxy-butoxy)-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, wasproduced as follows: A mixture of4-methyl-2-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one(16.5 g, 0.049 mol) and PPTS (1.24 g, 0.0049 mol) in ethanol (250 mL)and CH₂Cl₂ (20 mL) is stirred at room temperature for 16 h, followed byheating at reflux (˜90° C.) for 3 h. The cloudy reaction mixture isevaporated under vacuum and the residue is triturated in hexane-ethylacetate (150 mL, 1:1) and dried to give the third intermediate compoundas a yellow powder (12.5 g, 0.049 mol, 100%). MS: APCl: M+1: 250.0(Exact Mass: 249.11).

A fourth intermediate compound,4-(4-Methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde,was produced as follows: A stirred solution of IBX (26 g, 0.092 mol) inDMSO (220 ml) is treated with2-(4-hydroxy-butoxy)-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (11 g,0.0467 mol) portion wise while stirring at room temperature during 30min and the reaction is stirred at room temperature for an additional 2h. The mixture is cooled and treated with saturated NaHCO₃ (150 mL) andextracted with chloroform (4×0.5 L). The combined organic layer iswashed with brine/ice (2×), dried over Na₂SO₄, filtered andconcentrated. The residue is stirred with ether, filtered, washed withether and dried to give 6 g of the crude, which shows it to be amixture. The ether filtrate residue also shows some product, but mostlystarting material. The residue from the filtrate and the crude (11 g)are subjected to re-oxidation as above using fresh IBX (15.5 g, 0.055mol) in DMSO (150 mL), but stirred at 30° C. for 3 h. Workup as aboveyielded the fourth intermediate compound as an off-white powder (8.3 g,0.057 mol, 66.8%). MS: APCl: M+1: 248.0 (Exact Mass: 247.10).

The pyrimidines of Examples G10′-G15′ were synthesized in combinatoriallibrary format by reductive amination of the appropriate piperazinestarting materials with4-(4-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehydefollowing the general procedure outlined in Example C1′.

The title compound was isolated as a solid (81 mg, 0.179 mmol, 59.8%).MS: APCl: M+1: 452.3 (Exact Mass: 451.22).

Example G11′ Synthesis of2-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as a solid (56 mg, 0.128 mmol, 42.86%).MS: APCl: M+1: 436.3 (Exact Mass: 435.23).

Example G12′ Synthesis of2-[4-(4-Benzofuran-7-yl-piperazin-1-yl)-butoxy]-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as a white solid (56 mg, 0.129 mmol,43.06%). MS: APCl: M+1: 434.1 (Exact Mass: 433.21).

Example G13′ Synthesis of2-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as a white powder (53 mg, 0.117 mmol,39.3%). MS: APCl: M+1: 450.2 (Exact Mass: 449.24).

Example G14′ Synthesis of4-Methyl-2-{4-[4-(2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as a solid (58 mg, 0.125 mmol, 41.8%).MS: APCl: M+1: 463.2 (Exact Mass: 462.24).

Example G15′ Synthesis of4-Methyl-2-[4-(4-guinolin-8-yl-piperazin-1-yl)-butoxy]-8H-pyrido[2,3-d]pyrimidin-7-one

The title compound was isolated as a brown solid (44 mg, 0.099 mmol,32.9%). MS: APCl: M+1: 445.3 (Exact Mass: 444.23).

Example H1′ Synthesis of7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A first intermediate compound 3-(4,6-Diamino-pyridin-3-yl)-acrylic acidethyl ester, was produced as follows: A mixture of(carbethoxymethylene)triphenylphosphorane (436 g, 1.25 mol) and4,6-diaminopyridine-3-carbaldehyde (131.8 g, 0.96 mol) in 1,4-dioxane(2.0 L) was refluxed for 2.0 h. The mixture was cooled and filteredthrough silica gel (800 g) eluting with 0-10% MeOH/EtOAc. The filtratewas concentrated and the residue (˜580 g) was used in the next stepwithout further purification.

A second intermediate compound, 7-Amino-1H-[1,6]naphthyridin-2-one, wasproduced as follows: The residue obtained from the above procedure wasrefluxed in conc. HCl (1.5 L) for 1.5 h. The mixture was cooled anddiluted with water (2.5 L). At 35-40° C., the mixture was washed withEtOAc (3×). The aqueous layer was made basic with 50% NaOH to pH>10while cooling with a cold water bath. The resulting solid was collectedvia filtration, rinsed with water, methanol, and oven dried to affordthe second intermediate compound (106 g, 68% for two steps) as off-whitecrystals.

A third intermediate compound, 7-Fluoro-1H-[1,6]naphthyridin-2-one, wasproduced as follows: To a stirred mixture of HF-pyridine (660 g) and7-amino-1H-[1,6]naphthyridin-2-one (58 g, 0.36 mol) in a plastic bottlewas added NaNO₂ (39.7 g, 0.57 mol) in small portions over 30-40 minwhile cooled with a cold (˜10° C.) water bath in order to keep theinternal temperature at around RT. After the addition, the mixture wasfurther stirred at room temperature for 20 min before it was poured intowater (2.6 L) and stirred for 3.0 h. The resulting solid was collectedvia filtration, rinsed with water (2×), EtOAc-heptane (1:1, 2×), andoven dried to afford the third intermediate compound (48.6 g, 82%) aspale solid.

A fourth intermediate compound,7-(4-Benzyloxy-butoxy)-1H-[1,6]naphthyridin-2-one, was produced asfollows: A solution of 4-benzyloxy-butan-1-ol (35.98 g,199.6 mmol) andpotassium t-butoxide (21 g,188 mmol) in THF (60 mL) was prepared andstirred at room temperature for 20 min. A suspension of7-fluoro-1H-[1,6]naphthyridin-2-one (8.1 g, 49 mmol) in THF (100 mL) wasprepared, and the alcohol solution was added to this solution viacanula. The reaction was stirred at 80° C. overnight. MS showed mostlyproduct. So reaction quenched with saturated NH₄Cl and water. Thesolution was brought to a pH of 8 and extracted with ethyl acetate. Theorganic layer was washed with brine and concentrated to give a silkysolid. EtOAc was added and the mixture was filtered to give a beigesolid. The NMR indicated that it was the product and it wasrecrystallized from acetonitrile to give clean product. (9.70 g). Thefiltrate was concentrated and filtered to give more precipitate (0.788g). The filtrate was concentrated and purified by chromatography (0-70%EtOAc/hexanes) to give additional product as a beige solid (2.716 g).(Total Product: 13.21 g, 82%). MS: APCl: M+1: 325.2 (Exact Mass:324.15).

A fifth intermediate compound,7-(4-Hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one, wasproduced as follows: To a solution of7-(4-benzyloxy-butoxy)-1H-[1,6]naphthyridin-2-one (7.92 g, 24.4 mmol) inMeOH/THF (100 mL) was added 20% Pd/C (1.5 g) and the mixture washydrogenated for 59 h. The reaction was filtered, concentrated andpurified by liquid chromatography (0-10% MeOH/CH2Cl2) to give the fifthintermediate compound as a white solid (4.11 g, 17.4 mmol, 71%). MS:APCl: M+1: 237.1 (Exact Mass: 236.12).

A sixth intermediate compound,4-(2-Oxo-1,2,3,4-tetrahydro-[1,6]naphthyridin-7-yloxy)-butyraldehyde,was produced as follows: To a suspension of7-(4-hydroxy-butoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one (2.0 g, 8.5mmol) in dichloroethane (20 mL) was added IBX (7 g, 25 mmol). This washeated at 80° C. for 5 hours. The reaction was cooled and then filtered.The filter cake was washed with CH₂CH₂ until the product was removed.The filtrate was concentrated to give a yellow solid (1.88 g, used crudein next reaction). MS: APCl: M+1: 235.1 (Exact Mass: 234.10).

A reductive amination procedure similar to Example A1′ was followedusing 1-chroman-8-yl-piperazine (0.24 g; 69%). MS: APCl: M+1: 437.2(Exact Mass: 436.25).

Example H2′ Synthesis of7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 1-(2,3-dihydro-benzofuran-7-yl)-piperazine to give the titlecompound (0.32 g, 50%). MS: APCl: M+1: 423.2 (Exact Mass: 422.23).

Example H3′ Synthesis of7-{4-[4-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing1-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine togive the title compound (0.21 g, 27%). MS: APCl: M+1: 511.1 (Exact Mass:510.19).

Example H4′ Synthesis of7-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 1-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-piperazine to give thetitle compound (0.40 g, 56%). MS: APCl: M+1: 461.2 (Exact Mass: 460.19).

Example H5′ Synthesis of7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine to give the titlecompound (0.22 g, 50%). MS: APCl: M+1: 439.3 (Exact Mass: 438.23).

Example H6′ Synthesis of7-{4-[4-(2,3-Dihydro-benzofuran-7-yl)-piperazin-1-yl]-butoxy}-1H-[1,6]naphthyridin-2-one

A first intermediate compound7-(4-Hydroxy-butoxy)-1H-[1,6]naphthyridin-2-one, was produced asfollows: Butane-1,4-diol (8.24 g, 8.12 mL, 91.3 mmol) was added to solidKOtBu (6 g, 55 mmol). The very viscous mixture was stirred for 15 minbefore adding 7-fluoro-1H-[1,6]naphthyridin-2-one (3 g, 18 mmol). NMP(60 mL) was then added and the reaction was heated at 70° C. overnight.The reaction was cooled and poured into ice water. No precipitateformed, so the mixture was extracted with EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated. Purification bySiO₂ chromatography (0-50% EtOAc/Hex) gave the first intermediatecompound (2.36 g, 55%). MS: APCl: M+1: 235.0 (Exact Mass: 234.10).

A second intermediate compound,4-(2-Oxo-1,2-dihydro-[1,6]naphthyridin-7-yloxy)-butyraldehyde, wasproduced as follows: To a suspension of7-(4-hydroxy-butoxy)-1H-[1,6]naphthyridin-2-one (2.33 g, 9.95 mmol) indichloroethane (30 mL) was added IBX (8 g, 30 mmol) . The mixture washeated at 80° C. for 5 hours. The reaction was cooled and stirred, andthen filtered. The filter cake was washed with CH₂Cl₂ until the productwas removed. The filtrate was concentrated to give the secondintermediate compound as a yellow solid (2.45 g). MS: APCl: M+1: 233.1(Exact Mass: 232.08).

A reductive amination procedure similar to Example A1′ was followedusing 1-(2,3-dihydro-benzofuran-7-yl)-piperazine to give the titlecompound (0.225 g, 59%). MS: APCl: M+l: 421.2 (Exact Mass: 420.22).

Example H7′ Synthesis of7-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-butoxy}-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine to give the titlecompound (0.22 g, 60%). MS: APCl: M+1: 437.2 (Exact Mass: 436.21).

Example H8′ Synthesis of7-[4-(4-Chroman-8-yl-piperazin-1-yl)-butoxy]-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 1-chroman-8-yl-piperazine to give the title compound (0.23 g,62%). MS: APCl: M+1: 435.2 (Exact Mass: 434.23).

Example H9′ Synthesis of7-{4-[4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazin-1-yl]-butoxy}-1H-[1,6]naphthyridin-2-one

A reductive amination procedure similar to Example A1′ was followedusing 1-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-piperazine to give thetitle compound (0.26 g, 66%). MS: APCl: M+1: 459.2 (Exact Mass: 458.18).

1. A compound of formula 1

A is —(CH₂)_(m)CH₂—, —(CH₂)_(m)O—, or —(CH₂)_(m)NH—, wherein m is aninteger from 2 to 5 and wherein one or two of the carbon or nitrogenatoms of —(CH₂)_(m)CH₂—, —(CH₂)_(m)O— and —(CH₂)_(m)NH— can besubstituted, optionally and independently, with one or two substituentsthat are selected, independently, from fluoro and methyl, or with twosubstituents attached to the same carbon atom that form, together withthe carbon to which they are attached, a spirocyclopropyl orspirocyclobutyl ring; D is N, C, or CH, provided that when D is N eachcarbon atom covalently attached to D is attached through a single bond;Z and Q are independently N, C, or CH, provided that at least one of Zand Q is N; —X

Y— is —CH₂—CH₂—, —CH═CH—, —CH₂—NH—, —NH—CH₂—, —N═CH—, —CH═N—, —O—CH₂—,or —CH₂—O—, wherein —X

Y— can optionally be substituted, at any available bonding site, by oneto four substituents R², R²′, R³and R³′; V and W are independently N, C,or CH; ring AA is a saturated or unsaturated 5-6- or 7-memberedcarbocyclic ring wherein one, two or three of the carbon atoms of ringAA that are not shared with the benzo ring of group (ii) can bereplaced, optionally and independently, by a nitrogen, oxygen or sulfuratom; R¹ is hydrogen, —C(═O)CH₃, or (C₁-C₃) alkyl; R², R²′, R³ and R³′are independently selected from hydrogen, halo, cyano, oxo, hydroxy,—C(═O)CH₃, (C₁-C₄) alky, and (C₁-C₄) alkoxy, wherein the alkyl moietiesof the (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and —C(═O)CH₃ groups can beoptionally substituted with from one to three fluoro atoms and can alsobe optionally substituted with an amino or hydroxy substituent; R⁴ andR⁵ are independently selected from hydrogen, halo, cyano, hydroxy,—C(═O)CH₃, (C₁-C₄) alkyl, and (C₁-C₄) alkoxy, wherein the alkyl moietiesof the (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and —C(═O)CH₃ groups can beoptionally substituted with from one to three fluoro atoms and can alsobe optionally substituted with an amino or hydroxy substituent; R⁶ andR⁷ are selected, independently, from hydrogen and methyl; R⁸, R⁹, R¹⁰,R¹¹, and R¹² are independently selected from hydrogen, halo, —C(═O)CH₃,(C₁-C₄) alkyl, and (C₁-C₄) alkoxy, aryl, and aryloxy, wherein the alkylmoieties of the (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and —C(═O)CH₃ groups andthe aryl and aryoxy moieties can be optionally substituted with from oneto three fluoro atoms and can also be optionally substituted with anamino or hydroxy substituent; R¹³ and R¹⁴ are independently selectedfrom hydrogen, halo, cyano, oxo, hydroxy, —C(═O)CH₃, (C₁-C4) alkyl, and(C₁-C₄) alkoxy, wherein the alkyl moieties of the (C₁-C₄) alkyl, (C₁-C₄)alkoxy, and —C(═O)CH₃ groups can be optionally substituted with from oneto three fluoro atoms and can also be optionally substituted with anamino or hydroxy substituent; and the pharmaceutically acceptable saltsof such compounds.
 2. The compound or salt of claim 1, wherein Q is Nand Z is CH.
 3. The compound or salt of claim 1, wherein Q and Z areboth N.
 4. The compound or salt of claim 1, wherein W is CH.
 5. Thecompound or salt of claim 1, wherein —X

Y— is —CH₂—CH₂—.
 6. The compound or salt of claim 1, wherein —X

Y— is —CH═CH—.
 7. The compound or salt of claim 1, wherein D is N. 8.The compound or salt of claim 1, wherein R⁴ and R⁵ are hydrogen.
 9. Thecompound or salt of claim 1, wherein —X

Y— is —CH₂NH—.
 10. The compound or salt of claim 1, wherein D is N, Q isN, Z is CH, —X

Y— is —CH₂—CH₂— or —CH═CH—, and R¹, R⁴, and R⁵ are hydrogen.
 11. Thecompound or salt of claim 1, wherein W and V are C or CH, or only one ofW or V is N.
 12. The compound or salt of claim 1, wherein G is naphthyl,and R¹³ and R¹⁴ are independently hydrogen or flouro.
 13. The compoundor salt of claim 1, wherein at least one of R¹³ or R¹⁴ is flouro ormethoxy.
 14. The compound or salt of claim 1, wherein G is a group offormula:


15. The compound or salt of claim 1, wherein G is the group of formula(ii) and all atoms in ring AA are carbon atoms.
 16. The compound or saltof claim 15, wherein ring AA is benzo.
 17. The compound or salt of claim1, wherein G is a group of the formula (ii) and one, two, or threecarbons of the ring AA that are not shared by the benzo group of formula(ii) have been replaced by a nitrogen, oxygen or sulfur atom.
 18. Thecompound or salt of claim 1, wherein the compound or salt has a D₂intrinsic activity of about 20% to about 60%.
 19. The compound or saltof claim 1, selected from the group consisting of:7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;7-{4-[4-(8-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;7-{4-[4-(2-Methoxy-quinolin-8-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;7-{4-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;7-[4-(4-Indan-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one;7-{4-[4-(6,7-Difluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one;4-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;4,4-Dimethyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;5-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-5-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one;6-Fluoro-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-[1,8]naphthyridin-2-one;7-[4-(4-Benzo[1,2,5]thiadiazol-4-yl-piperazin-1-yl)-butoxy]-1H-[1,8]naphthyridin-2-one;7-[4-(4-Naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;3-Methyl-7-[4-(4-naphthalen-1-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one;7-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,6]naphthyridin-2-one;2-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-8H-pyrido[2,3-d]pyrimidin-7-one;and6-{4-[4-(7-Fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-4H-pyrido[3,2-b][1,4]oxazin-3-one.20. A pharmaceutical composition for treating a disorder or conditionselected from single episodic or recurrent major depressive disorders,dysthymic disorders, depressive neurosis and neurotic depression,melancholic depression including anorexia, weight loss, insomnia, earlymorning waking or psychomotor retardation; atypical depression (orreactive depression) including increased appetite, hypersomnia,psychomotor agitation or irritability, seasonal affective disorder andpediatric depression; bipolar disorders or manic depression, forexample, bipolar I disorder, bipolar II disorder and cyclothymicdisorder; conduct disorder; disruptive behavior disorder; attentiondeficit hyperactivity disorder (ADHD); behavioral disturbancesassociated with mental retardation, autistic disorder, and conductdisorder; anxiety disorders such as panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobias, for example, specific animal phobias, social anxiety, socialphobia, obsessive-compulsive disorder, stress disorders includingpost-traumatic stress disorder and acute stress disorder, andgeneralized anxiety disorders; borderline personality disorder;schizophrenia and other psychotic disorders, for example,schizophreniform disorders, schizoaffective disorders, delusionaldisorders brief psychotic disorders, shared psychotic disorders,psychotic disorders with delusions or hallucinations, psychotic episodesof anxiety, anxiety associated with psychosis, psychotic mood disorderssuch as severe major depressive disorder; mood disorders associated withpsychotic disorders such as acute mania and depression associated withbipolar disorder; mood disorders associated with schizophrenia;delirium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Parkinson's disease (PD),Huntington's disease (HD), Alzheimer's disease, senile dementia,dementia of the Alzheimer's type, memory disorders, loss of executivefunction, vascular dementia, and other dementias, for example, due toHIV disease, head trauma, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeldt-Jakob disease, or due to multipleetiologies; movement disorders such as akinesias, dyskinesias, includingfamilial paroxysmal dyskinesias, spasticities, Tourette's syndrome,Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidalmovement disorders such as medication-induced movement disorders, forexample, neuroleptic-induced Parkinsonism, neuroleptic malignantsyndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acuteakathisia, neuroleptic-induced tardive dyskinesia and medication-inducedpostural tremour; chemical dependencies and addictions (e.g.,dependencies on, or addictions to, alcohol, heroin, cocaine,benzodiazepines, nicotine, or phenobarbitol) and behavioral addictionssuch as an addiction to gambling; and ocular disorders such as glaucomaand ischemic retinopathy in a mammal, including a human, comprising: anamount of a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, that is effective in treating such disorder orcondition, and a pharmaceutically acceptable carrier.
 21. A method fortreating a disorder or condition selected from single episodic orrecurrent major depressive disorders, dysthymic disorders, depressiveneurosis and neurotic depression, melancholic depression includinganorexia, weight loss, insomnia, early morning waking or psychomotorretardation; atypical depression (or reactive depression) includingincreased appetite, hypersomnia, psychomotor agitation or irritability,seasonal affective disorder and pediatric depression; bipolar disordersor manic depression, for example, bipolar I disorder, bipolar IIdisorder and cyclothymic disorder; conduct disorder; disruptive behaviordisorder; attention deficit hyperactivity disorder (ADHD); behavioraldisturbances associated with mental retardation, autistic disorder, andconduct disorder; anxiety disorders such as panic disorder with orwithout agoraphobia, agoraphobia without history of panic disorder,specific phobias, for example, specific animal phobias, social anxiety,social phobia, obsessive-compulsive disorder, stress disorders includingpost-traumatic stress disorder and acute stress disorder, andgeneralized anxiety disorders; borderline personality disorder;schizophrenia and other psychotic disorders, for example,schizophreniform disorders, schizoaffective disorders, delusionaldisorders brief psychotic disorders, shared psychotic disorders,psychotic disorders with delusions or hallucinations, psychotic episodesof anxiety, anxiety associated with psychosis, psychotic mood disorderssuch as severe major depressive disorder; mood disorders associated withpsychotic disorders such as acute mania and depression associated withbipolar disorder; mood disorders associated with schizophrenia;delirium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Parkinson's disease (PD),Huntington's disease (HD), Alzheimer's disease, senile dementia,dementia of the Alzheimer's type, memory disorders, loss of executivefunction, vascular dementia, and other dementias, for example, due toHIV disease, head trauma, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeldt-Jakob disease, or due to multipleetiologies; movement disorders such as akinesias, dyskinesias, includingfamilial paroxysmal dyskinesias, spasticities, Tourette's syndrome,Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidalmovement disorders such as medication-induced movement disorders, forexample, neuroleptic-induced Parkinsonism, neuroleptic malignantsyndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acuteakathisia, neuroleptic-induced tardive dyskinesia and medication-inducedpostural tremour; chemical dependencies and addictions (e.g.,dependencies on, or addictions to, alcohol, heroin, cocaine,benzodiazepines, nicotine, or phenobarbitol) and behavioral addictionssuch as an addiction to gambling; and ocular disorders such as glaucomaand ischemic retinopathy in a mammal, including a human, comprising:administering to a mammal in need of such treatment an amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof, thatis effective in treating the disorder or condition.
 22. The method ofclaim 21, wherein the disorder or condition that is being treated isselected from the group consisting of: major depression, single episodedepression, recurrent depression, child abuse induced depression,postpartum depression, dysthymia, cyclothymia and bipolar disorder. 23.The method of claim 21, wherein the disorder or condition that is beingtreated is selected from the group consisting of: schizophrenia,schizoaffective disorder, delusional disorder, substance-inducedpsychotic disorder, brief psychotic disorder, shared psychotic disorder,psychotic disorder due to a general medical condition, andschizophreniform disorder.
 24. The method of claim 21, wherein thedisorder or condition that is being treated is selected from autism,pervasive development disorder, and attention deficit hyperactivitydisorder.
 25. The method of claim 21, wherein the disorder or conditionthat is being treated is selected from generalized anxiety disorder,panic disorder, obsessive-compulsive disorder, post-traumatic stressdisorder, and phobias, including social phobia, agoraphobia, andspecific phobias.
 26. The method of claim 21, wherein the compoundaccording to claim 1 is administered to a human for the treatment of anytwo or more comorbid disorders or conditions selected from thosedisorders and conditions referred to in any of the above methods. 27.The method of claim 21, wherein the disorder or condition being treatedis schizophrenia with concomitant depression.
 28. The method of claim21, wherein the disorder or condition being treated is schizophreniawith concomitant anxiety.
 29. A method of treating a disorder orcondition selected from single episodic or recurrent major depressivedisorders, dysthymic disorders, depressive neurosis and neuroticdepression, melancholic depression including anorexia, weight loss,insomnia, early morning waking or psychomotor retardation; atypicaldepression (or reactive depression) including increased appetite,hypersomnia, psychomotor agitation or irritability, seasonal affectivedisorder and pediatric depression; bipolar disorders or manicdepression, for example, bipolar I disorder, bipolar II disorder andcyclothymic disorder; conduct disorder; disruptive behavior disorder;attention deficit hyperactivity disorder (ADHD); behavioral disturbancesassociated with mental retardation, autistic disorder, and conductdisorder; anxiety disorders such as panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobias, for example, specific animal phobias, social anxiety, socialphobia, obsessive-compulsive disorder, stress disorders includingpost-traumatic stress disorder and acute stress disorder, andgeneralized anxiety disorders; borderline personality disorder;schizophrenia and other psychotic disorders, for example,schizophreniform disorders, schizoaffective disorders, delusionaldisorders, brief psychotic disorders, shared psychotic disorders,psychotic disorders with delusions or hallucinations, psychotic episodesof anxiety, anxiety associated with psychosis, psychotic mood disorderssuch as severe major depressive disorder; mood disorders associated withpsychotic disorders such as acute mania and depression associated withbipolar disorder; mood disorders associated with schizophrenia;delirium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Parkinson's disease (PD),Huntington's disease (HD), Alzheimer's disease, senile dementia,dementia of the Alzheimer's type, memory disorders, loss of executivefunction, vascular dementia, and other dementias, for example, due toHIV disease, head trauma, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeldt-Jakob disease, or due to multipleetiologies; movement disorders such as akinesias, dyskinesias, includingfamilial paroxysmal dyskinesias, spasticities, Tourette's syndrome,Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidalmovement disorders such as medication-induced movement disorders, forexample, neuroleptic-induced Parkinsonism, neuroleptic malignantsyndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acuteakathisia, neuroleptic-induced tardive dyskinesia and medication-inducedpostural tremour; chemical dependencies and addictions (e.g.,dependencies on, or addictions to, alcohol, heroin, cocaine,benzodiazepines, nicotine, or phenobarbitol) and behavioral addictionssuch as an addiction to gambling; and ocular disorders such as glaucomaand ischemic retinopathy in a mammal, including a human, comprisingadministering to said mammal: active agent (a), a compound of claim 1,or a pharmaceutically acceptable salt thereof; and active agent (b),another pharmaceutically active compound that is an antidepressant or ananti-anxiety agent, or a pharmaceutically acceptable salt thereof;wherein the active agents (a) and (b) are present in amounts that renderthe combination effective in treating such disorder or condition.
 30. Apharmaceutical composition for treating a disorder or condition selectedfrom single episodic or recurrent major depressive disorders, dysthymicdisorders, depressive neurosis and neurotic depression, melancholicdepression including anorexia, weight loss, insomnia, early morningwaking or psychomotor retardation; atypical depression (or reactivedepression) including increased appetite, hypersomnia, psychomotoragitation or irritability, seasonal affective disorder and pediatricdepression; bipolar disorders or manic depression, for example, bipolarI disorder, bipolar II disorder and cyclothymic disorder; conductdisorder; disruptive behavior disorder; attention deficit hyperactivitydisorder (ADHD); behavioral disturbances associated with mentalretardation, autistic disorder, and conduct disorder; anxiety disorderssuch as panic disorder with or without agoraphobia, agoraphobia withouthistory of panic disorder, specific phobias, for example, specificanimal phobias, social anxiety, social phobia, obsessive-compulsivedisorder, stress disorders including post-traumatic stress disorder-andacute stress disorder, and generalized anxiety disorders; borderlinepersonality disorder; schizophrenia and other psychotic disorders, forexample, schizophreniform disorders, schizoaffective disorders,delusional disorders brief psychotic disorders, shared psychoticdisorders, psychotic disorders with delusions or hallucinations,psychotic episodes of anxiety, anxiety associated with psychosis,psychotic mood disorders such as severe major depressive disorder; mooddisorders associated with psychotic disorders such as acute mania anddepression associated with bipolar disorder; mood disorders associatedwith schizophrenia; delirium, dementia, and amnestic and other cognitiveor neurodegenerative disorders, such as Parkinson's disease (PD),Huntington's disease (HD), Alzheimer's disease, senile dementia,dementia of the Alzheimer's type, memory disorders, loss of executivefunction, vascular dementia, and other dementias, for example, due toHIV disease, head trauma, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeldt-Jakob disease, or due to multipleetiologies; movement disorders such as akinesias, dyskinesias, includingfamilial paroxysmal dyskinesias, spasticities, Tourette's syndrome,Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidalmovement disorders such as medication-induced movement disorders, forexample, neuroleptic-induced Parkinsonism, neuroleptic malignantsyndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acuteakathisia, neuroleptic-induced tardive dyskinesia and medication-inducedpostural tremour; chemical dependencies and addictions (e.g.,dependencies on, or addictions to, alcohol, heroin, cocaine,benzodiazepines, nicotine, or phenobarbitol) and behavioral addictionssuch as an addiction to gambling; and ocular disorders such as glaucomaand ischemic retinopathy in a mammal comprising: active agent (a), acompound according to claim 1, or a pharmaceutically acceptable saltthereof; active agent (b), another pharmaceutically active agent that isan antidepressant or an anti-anxiety agent; and a pharmaceuticallyacceptable carrier.
 31. The method of claim 30, wherein the disorder orcondition being treated is schizophrenia.
 32. The method of claim 30,wherein the disorder or condition that is being treated is selected fromschizophrenia, schizoaffective disorder, delusional disorder,substance-induced psychotic disorder, brief psychotic disorder, sharedpsychotic disorder, psychotic disorder due to a general medicalcondition, and schizophreniform disorder.
 33. The method of claim 30,wherein the disorder or condition that is being treated is selected fromautism, pervasive development disorder, and attention deficithyperactivity disorder.
 34. The method of claim 30, wherein the disorderor condition that is being treated is selected from generalized anxietydisorder, panic disorder, obsessive-compulsive disorder, post-traumaticstress disorder, and phobias, including social phobia, agoraphobia, andspecific phobias.
 35. The method of claim 30, wherein the active agent(a) and the active agent (b) are administered to a human for thetreatment of any two or more comorbid disorders or conditions selectedfrom those disorders and conditions referred to in any of the abovemethods.
 36. The method of claim 30, wherein the disorder or conditionbeing treated is schizophrenia with concomitant depression.
 37. Themethod of claim 30, wherein the disorder or condition being treated isschizophrenia with concomitant anxiety.
 38. A pharmaceutical compositionfor treating a disorder or condition selected from single episodic orrecurrent major depressive disorders, dysthymic disorders, depressiveneurosis and neurotic depression, melancholic depression includinganorexia, weight loss, insomnia, early morning waking or psychomotorretardation; atypical depression (or reactive depression) includingincreased appetite, hypersomnia, psychomotor agitation or irritability,seasonal affective disorder and pediatric depression; bipolar disordersor manic depression, for example, bipolar I disorder, bipolar IIdisorder and cyclothymic disorder; conduct disorder; disruptive behaviordisorder; attention deficit hyperactivity disorder (ADHD); behavioraldisturbances associated with mental retardation, autistic disorder, andconduct disorder; anxiety disorders such as panic disorder with orwithout agoraphobia, agoraphobia without history of panic disorder,specific phobias, for example, specific animal phobias, social anxiety,social phobia, obsessive-compulsive disorder, stress disorders includingpost-traumatic stress disorder and acute stress disorder, andgeneralized anxiety disorders; borderline personality disorder;schizophrenia and other psychotic disorders, for example,schizophreniform disorders, schizoaffective disorders, delusionaldisorders brief psychotic disorders, shared psychotic disorders,psychotic disorders with delusions or hallucinations, psychotic episodesof anxiety, anxiety associated with psychosis, psychotic mood disorderssuch as severe major depressive disorder; mood disorders associated withpsychotic disorders such as acute mania and depression associated withbipolar disorder; mood disorders associated with schizophrenia;delirium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Parkinson's disease (PD),Huntington's disease (HD), Alzheimer's disease, senile dementia,dementia of the Alzheimer's type, memory disorders, loss of executivefunction, vascular dementia, and other dementias, for example, due toHIV disease, head trauma, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeldt-Jakob disease, or due to multipleetiologies; movement disorders such as akinesias, dyskinesias, includingfamilial paroxysmal dyskinesias, spasticities, Tourette's syndrome,Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidalmovement disorders such as medication-induced movement disorders, forexample, neuroleptic-induced Parkinsonism, neuroleptic malignantsyndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acuteakathisia, neuroleptic-induced tardive dyskinesia and medication-inducedpostural tremour; chemical dependencies and addictions (e.g.,dependencies on, or addictions to, alcohol, heroin, cocaine,benzodiazepines, nicotine, or phenobarbitol) and behavioral addictionssuch as an addiction to gambling; and ocular disorders such as glaucomaand ischemic retinopathy in a mammal, including a human, comprising anamount of a compound according to claim 19, or a pharmaceuticallyacceptable salt thereof, that is effective in treating such disorder orcondition, and a pharmaceutically acceptable carrier.
 39. A method fortreating a disorder or condition selected from single episodic orrecurrent major depressive disorders, dysthymic disorders, depressiveneurosis and neurotic depression, melancholic depression includinganorexia, weight loss, insomnia, early morning waking or psychomotorretardation; atypical depression (or reactive depression) includingincreased appetite, hypersomnia, psychomotor agitation or irritability,seasonal affective disorder and pediatric depression; bipolar disordersor manic depression, for example, bipolar I disorder, bipolar IIdisorder and cyclothymic disorder; conduct disorder; disruptive behaviordisorder; attention deficit hyperactivity disorder (ADHD); behavioraldisturbances associated with mental retardation, autistic disorder, andconduct disorder; anxiety disorders such as panic disorder with orwithout agoraphobia, agoraphobia without history of panic disorder,specific phobias, for example, specific animal phobias, social anxiety,social phobia, obsessive-compulsive disorder, stress disorders includingpost-traumatic stress disorder and acute stress disorder, andgeneralized anxiety disorders; borderline personality disorder;schizophrenia and other psychotic disorders, for example,schizophreniform disorders, schizoaffective disorders, delusionaldisorders brief psychotic disorders, shared psychotic disorders,psychotic disorders with delusions or hallucinations, psychotic episodesof anxiety, anxiety associated with psychosis, psychotic mood disorderssuch as severe major depressive disorder; mood disorders associated withpsychotic disorders such as acute mania and depression associated withbipolar disorder; mood disorders associated with schizophrenia;delirium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Parkinson's disease (PD),Huntington's disease (HD), Alzheimer's disease, senile dementia,dementia of the Alzheimer's type, memory disorders, loss of executivefunction, vascular dementia, and other dementias, for example, due toHIV disease, head trauma, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeldt-Jakob disease, or due to multipleetiologies; movement disorders such as akinesias, dyskinesias, includingfamilial paroxysmal dyskinesias, spasticities, Tourette's syndrome,Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidalmovement disorders such as medication-induced movement disorders, forexample, neuroleptic-induced Parkinsonism, neuroleptic malignantsyndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acuteakathisia, neuroleptic-induced tardive dyskinesia and medication-inducedpostural tremour; chemical dependencies and addictions (e.g.,dependencies on, or addictions to, alcohol, heroin, cocaine,benzodiazepines, nicotine, or phenobarbitol) and behavioral addictionssuch as an addiction to gambling; and ocular disorders such as glaucomaand ischemic retinopathy in a mammal, including a human, comprisingadministering to a mammal in need of such treatment an amount of acompound according to claim 19, or a pharmaceutically acceptable saltthereof, that is effective in treating such disorder or condition. 40.The method of claim 39, wherein the disorder or condition that is beingtreated is selected from major depression, single episode depression,recurrent depression, child abuse induced-depression, postpartumdepression, dysthymia, cyclothymia and bipolar disorder.
 41. The methodof claim 39, wherein the disorder or condition that is being treated isselected from schizophrenia, schizoaffective disorder, delusionaldisorder, substance-induced psychotic disorder, brief psychoticdisorder, shared psychotic disorder, psychotic disorder due to a generalmedical condition, and schizophreniform disorder.
 42. The method ofclaim 39, wherein the disorder or condition that is being treated isselected from autism, pervasive development disorder, and attentiondeficit hyperactivity disorder (ADHD).
 43. The method of claim 39,wherein the disorder or condition that is being treated is selected fromgeneralized anxiety disorder, panic disorder, obsessive-compulsivedisorder, post-traumatic stress disorder, and phobias, including socialphobia, agoraphobia, and specific phobias.
 44. The method of claim 39,wherein the compound of claim 8 is administered to a human for thetreatment of any two or more comorbid disorders or conditions selectedfrom those disorders and conditions referred to in any of the abovemethods.
 45. The method of claim 39, wherein the disorder or conditionbeing treated is schizophrenia with concomitant depression.
 46. Themethod of claim 39, wherein the disorder or condition being treated isschizophrenia with concomitant anxiety.
 47. A method of treating adisorder or condition selected from single episodic or recurrent majordepressive disorders, dysthymic disorders, depressive neurosis andneurotic depression, melancholic depression including anorexia, weightloss, insomnia, early morning waking or psychomotor retardation;atypical depression (or reactive depression) including increasedappetite, hypersomnia, psychomotor agitation or irritability, seasonalaffective disorder and pediatric depression; bipolar disorders or manicdepression, for example, bipolar I disorder, bipolar II disorder andcyclothymic disorder; conduct disorder; disruptive behavior disorder;attention deficit hyperactivity disorder (ADHD); behavioral disturbancesassociated with mental retardation, autistic disorder, and conductdisorder; anxiety disorders such as panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobias, for example, specific animal phobias, social anxiety, socialphobia, obsessive-compulsive disorder, stress disorders includingpost-traumatic stress disorder and acute stress disorder, andgeneralized anxiety disorders; borderline personality disorder;schizophrenia and other psychotic disorders, for example,schizophreniform disorders, schizoaffective disorders, delusionaldisorders, brief psychotic disorders, shared psychotic disorders,psychotic disorders with delusions or hallucinations, psychotic episodesof anxiety, anxiety associated with psychosis, psychotic mood disorderssuch as severe major depressive disorder; mood disorders associated withpsychotic disorders such as acute mania and depression associated withbipolar disorder; mood disorders associated with schizophrenia;delirium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Parkinson's disease (PD),Huntington's disease (HD), Alzheimer's disease, senile dementia,dementia of the Alzheimer's type, memory disorders, loss of executivefunction, vascular dementia, and other dementias, for example, due toHIV disease, head trauma, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeldt-Jakob disease, or due to multipleetiologies; movement disorders such as akinesias, dyskinesias, includingfamilial paroxysmal dyskinesias, spasticities, Tourefte's syndrome,Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidalmovement disorders such as medication-induced movement disorders, forexample, neuroleptic-induced Parkinsonism, neuroleptic malignantsyndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acuteakathisia, neuroleptic-induced tardive dyskinesia and medication-inducedpostural tremour; chemical dependencies and addictions (e.g.,dependencies on, or addictions to, alcohol, heroin, cocaine,benzodiazepines, nicotine, or phenobarbitol) and behavioral addictionssuch as an addiction to gambling; and ocular disorders such as glaucomaand ischemic retinopathy in a mammal, including a human, comprisingadministering to said mammal: active compound (a), a compound accordingto claim 19 or a pharmaceutically acceptable salt thereof; and activecompound (b), another pharmaceutically active compound that is anantidepressant or an anti-anxiety agent, or a pharmaceuticallyacceptable salt thereof; wherein the active agent (a) and the activeagent (b) are present in amounts that render the combination effectivein treating such disorder or condition.
 48. A pharmaceutical compositionfor treating a disorder or condition selected from single episodic orrecurrent major depressive disorders, dysthymic disorders, depressiveneurosis and neurotic depression, melancholic depression includinganorexia, weight loss, insomnia, early morning waking or psychomotorretardation; atypical depression (or reactive depression) includingincreased appetite, hypersomnia, psychomotor agitation or irritability,seasonal affective disorder and pediatric depression; bipolar disordersor manic depression, for example, bipolar I disorder, bipolar IIdisorder and cyclothymic disorder; conduct disorder; disruptive behaviordisorder; attention deficit hyperactivity disorder (ADHD); behavioraldisturbances associated with mental retardation, autistic disorder, andconduct disorder; anxiety disorders such as panic disorder with orwithout agoraphobia, agoraphobia without history of panic disorder,specific phobias, for example, specific animal phobias, social anxiety,social phobia, obsessive-compulsive disorder, stress disorders includingpost-traumatic stress disorder and acute stress disorder, andgeneralized anxiety disorders; borderline personality disorder;schizophrenia and other psychotic disorders, for example,schizophreniform disorders, schizoaffective disorders, delusionaldisorders brief psychotic disorders, shared psychotic disorders,psychotic disorders with delusions or hallucinations, psychotic episodesof anxiety, anxiety associated with psychosis, psychotic mood disorderssuch as severe major depressive disorder; mood disorders associated withpsychotic disorders such as acute mania and depression associated withbipolar disorder; mood disorders associated with schizophrenia;delirium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Parkinson's disease (PD),Huntington's disease (HD), Alzheimer's disease, senile dementia,dementia of the Alzheimer's type, memory disorders, loss of executivefunction, vascular dementia, and other dementias, for example, due toHIV disease, head trauma, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeldt-Jakob disease, or due to multipleetiologies; movement disorders such as akinesias, dyskinesias, includingfamilial paroxysmal dyskinesias, spasticities, Tourette's syndrome,Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidalmovement disorders such as medication-induced movement disorders, forexample, neuroleptic-induced Parkinsonism, neuroleptic malignantsyndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acuteakathisia, neuroleptic-induced tardive dyskinesia and medication-inducedpostural tremour; chemical dependencies and addictions (e.g.,dependencies on, or addictions to, alcohol, heroin, cocaine,benzodiazepines, nicotine, or phenobarbitol) and behavioral addictionssuch as an addiction to gambling; and ocular disorders such as glaucomaand ischemic retinopathy in a mammal comprising: active agent (a), acompound according to claim 19 or a pharmaceutically acceptable saltthereof; active agent (b), another pharmaceutically active agent that isan antidepressant or an anti-anxiety agent; and a pharmaceuticallyacceptable carrier.
 49. The method of claim 48, wherein the disorder orcondition being treated is schizophrenia.
 50. The method of claim 48,wherein the disorder or condition that is being treated is selected fromschizophrenia, schizoaffective disorder, delusional disorder,substance-induced psychotic disorder, brief psychotic disorder, sharedpsychotic disorder, psychotic disorder due to a general medicalcondition, and schizophreniform disorder.
 51. The method of claim 48,wherein the disorder or condition that is being treated is selected fromautism, pervasive development disorder, and attention deficithyperactivity disorder.
 52. The method of claim 48, wherein the disorderor condition that is being treated is selected from generalized anxietydisorder, panic disorder, obsessive-compulsive disorder, post-traumaticstress disorder, and phobias, including social phobia, agoraphobia, andspecific phobias.
 53. The method of claim 48, wherein the active agents(a) and (b) are administered to a human for the treatment of any two ormore comorbid disorders or conditions selected from those disorders andconditions referred to in any of the above methods.
 54. The method ofclaim 48, wherein the disorder or condition being treated isschizophrenia with concomitant depression.
 55. The method of claim 48,wherein the disorder or condition being treated is schizophrenia withconcomitant anxiety.
 56. A process for preparing a compound of formula6:

wherein P is H or a protecting group n is an integer from 1 to 4; and Z,Q, X, Y, R¹, R⁴, R⁵ are defined as claim 1; comprising, reacting acompound of formula 5:

wherein Q, Z, X, Y, R¹, R⁴, and R⁵ are defined as above; and R¹³ is Cl,F, Br, S(O)Me, SO₂Me, or OSO₂CF₃ with a compound of formula:PO(CH₂)_(n)CH₂OH, wherein P is defined as above, in the presence of abase and a phase transfer catalyst.
 57. The process of claim 56, whereinthe protecting group is benzyl.
 58. The process of claim 56, wherein theprotecting group is a substituted benzyl.
 59. The process of claim 56,wherein the substituted benzyl is selected from the group consisting of2-, 3-, or 4-monomethoxybenzyl; 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or3,5-dimethoxybenzyl; 2,4,6-, or 3,4,5-trimethoxybenzyl; mono C-1,6-, n-,iso-, or branched-alkylbenzyl; 1-phenethyl; 2-phenethyl; mono F—, Cl—,or Br— benzyl; 2- or 4-methoxyphenyl; 2,4- or 2,6-dimethoxyphenyl; abenzyl substituted with diphenylmethyl-, trityl-, or trialkylsilyl- ofthe formula R₁₅, R₁₆, R₁₇Si, where R₁₅, R₁₆, and R₁₇ are independentlyC₁ to C₆, or n-, iso-, branched-alkyl-, or phenyl.
 60. The process ofclaim 56, wherein the protecting group is an acetal.
 61. The process ofclaim 60, wherein the acetal is selected from the group consisting of:tetrahydropyranyl and acetals of the general formula CHR₁₈OR₁₉, whereR₁₈ is H, phenyl, benzyl, or C₁ to C₆, n, iso, or branched alkyl, andR₁₉ is C₁ to C₆, n, iso, or branched alkyl, phenyl, or benzyl;2-(trimethylsilyl) methyxomethyl, 2-methoxyethoxymethyl, andtrichloroethyoxymethyl acetals.
 62. The process of claim 56, wherein theprotecting group is selected from the group consisting ofp-methoxybenzyl, tert-butyidimethylsilyl, and tetryhydropyranyl.
 63. Theprocess of claim 56, wherein the phase transfer catalyst is selectedfrom the group consisting of a tetraalkyl or benzalkylammonium chlorideor bromide of the general formula R₂₀R₂₁R₂₂R₂₃NX, where X isindependently Cl or Br, and R₂₀, R₂₁, R₂₂, and R₂₃ are eachindependently C₁ through C₁₈, normal, iso, or branched chain alkyl,benzyl, or mono or multiply C₁ through C₁₈, normal, iso, or branchedchain alkyl substituted benzyl, or singly or multiply halogen or alkoxysubstituted benzyl.
 64. The process of claim 56, wherein the phasetransfer catalyst is selected from the group consisting of: tetran-butylammonium chloride or bromide, benzyltrimethylammonium bromide orchloride, methyltrioctylammonium chloride or bromide, andtributylmethylammonium chloride or bromide.
 65. The process of claim 56,wherein the phase transfer catalyst is tetrabutyl ammonium chloride orbromide.
 66. The process of claim 56, wherein the base is selected fromthe group consisting of sodium hydride, potassium hydride, lithiumt-butoxide, sodium t-butoxide, potassium t-butoxide, lithium t-amylate,sodium t-amylate, and potassium t-amylate.
 67. The process of claim 56,wherein the base is potassium t-butoxide or sodium t-butoxide.
 68. Theprocess of claim 56, wherein the reaction of the compound of formula 5is further carried out in the presence of a reaction solvent.
 69. Theprocess of claim 68, wherein the reaction solvent has a refluxtemperature, and reaction is carried out at a reaction temperature ofabout 25° C. to the reflux temperature of the reaction solvent.
 70. Theprocess of claim 69, wherein the reaction temperature is about 25° C.71. The process of claim 69, where in the reaction solvent is selectedfrom the group consisting of: tetrahydrafuran, N-methyl-2-pyrrolidinone,N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfite,acetonitrile, propionitrile, isobutyronitrile, 1,2-dimethyoxethane,diethyleneglycoldimethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran,2,5 dimethyltetrahydrofuran, methyl t-butylether, and anisole.
 72. Theprocess of claim 68, where in the reaction solvent is tetrahydrafuran.73. The process of claim 56, wherein R¹³ of formula 5 is F.
 74. Theprocess of claim 73, wherein —X

Y— is CH═CH or CH₂—CH₂.
 75. A process for preparing the compound ofclaim 1, wherein A of formula 1 is —(CH₂)_(m)O— and m is an integer from2 to 5, the process comprising reacting a compound of formula 4a:

wherein n is an integer from 1 to 4, Q, Z, —X

Y—, R¹, R⁴, and R⁵ are defined as in claim 1, with a compound of thefollowing formula, in the presence of a base:

wherein G and D are defined as in claim
 1. 76. The process of claim 75,wherein the base does not react with the compound of formula 4a, and issufficiently basic to absorb HCl produced in the reaction.
 77. Theprocess of claim 75 where the base is selected from the group consistingof: diisopropylethylamine, diisopropylisobutylamine,4-diisopropylmorpholine, N,N,-diisopropylaniline,2,6-diisopropylpyridine, 2,6-di-t-butylpyridine,2,6-di-t-butyl-4-methylpyridine, lithium carbonate, sodium carbonate,potassium carbonate, rubidium carbonate, cesium carbonate, calciumcarbonate, magnesium carbonate, lithium bicarbobate, sodium bicarbonate,potassium bicarbonate, rubidium bicarbonate, cesium bicarbonate, calciumoxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, andpotassium phosphate.
 78. The process of claim 75, wherein the base isselected from the group consisting of diisopropylethylamine, potassiumcarbonate, and sodium carbonate.
 79. The process of claim 75, whereinthe reaction is carried out in the presence of a reaction solvent. 80.The process of claim 79, wherein the reaction solvent is selected fromthe group consisting of acetonitrile, propionitrile, isobutyronitrile,2-methoxyethanol, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydofuran,1,2-dimethoxyethane, diethyleneglycol dimethyl ether, water, anddichloromethane.
 81. The process of claim 79, wherein the reactionsolvent is water.
 82. The process of claim 81, wherein the reaction iscarried out at a reaction temperature from about 25° C. to about thereflux temperature of water.
 83. The process of claim 82, wherein thereaction is carried out at about the reflux temperature of water. 84.The process of claim 75, wherein n is
 3. 85. A process for preparing thecompound of claim 1, comprising reacting a compound of formula 3:

wherein n is an integer from 1 to 4; and Z, Q, X, Y, R¹, R⁴, R⁵ aredefined as in claim 1; with a compound of the following formula,

wherein G and D are defined as in claim 1, in a reductive aminationreaction.
 86. The process of claim 85, further comprising an oxidationstep, wherein the compound of formula 3 used in the reductive aminationreaction is produced by oxidizing a compound of formula 2:

wherein n, Z, Q, X, Y, R¹, R⁴, and R⁵ are defined as claim 84; in thepresence of an oxidant.
 87. The process of claim 86, wherein the oxidantis selected from the group consisting of: a Dess Martin oxidant,periodinane, iodoxybenzoic acid, activated dimethylsulfite, pyridiniumchlorochromate, and tetra n-propylruthenate-4-N-methylmorpholine-Noxide.
 88. The process of claim 86, wherein the oxidant is a combinationof 2,2,6,6-tetramethyl-1-piperidinyloxide (TEMPO) or a substituted TEMPOreagent and a stoichiometeric oxidant, wherein the stoichiometericoxidant is selected from the group consisting of sodium hypochlorite,trichloroisocyanuric acid, iodobenzene diacetate, N-chlorosuccinimide,N-bromosuccinimide, dimethyldichlorohydantoin, anddimethyidibromohydantoin.
 89. The process of claim 86, wherein theoxidant is 2-iodoxybenzoic acid.
 90. The process of claim 86, whereinthe oxidation step is carried out in the presence of a solvent.
 91. Theprocess of claim 90, wherein the solvent is selected from the groupconsisting of dichloromethane, 1,2-dichloroethane, ethylacetate,tetrahydrofuran, acetonitrile, dimethylsulfite, and a combination of twoor more of these solvents.
 92. The process of claim 90 where the solventis dimethylsulfite.
 93. The process of claim 86, wherein the oxidationstep is carried out using a process selected from the group consistingof a Dess Martin oxidation reaction, a Swern oxidation reaction, and aMoffat oxidation reaction.
 94. The process of claim 85, furthercomprising using a catalytic hydrogenation process in the reductiveamination step, using molecular hydrogen and a metal catalyst.
 95. Theprocess of claim 94, wherein the metal catalyst is selected from thegroup consisting of a platinum catalyst, a palladium catalyst, and aRaney nickel group catalyst.
 96. The process of claim 94, wherein ahydride donor is used in the catalytic hydrogenation process.
 97. Theprocess of claim 96, wherein the hydride donor is selected from thegroup consisting of formic acid, triethylammonium formate, cyclohexeneor substituted cyclohexenes, and cyclohexadiene or substitutedcyclohexadienes.
 98. The process of claim 85, wherein a hydride reducingagent is used in the reductive amination reaction.
 99. The process ofclaim 98, wherein the hydride reducing agent is selected from the groupconsisting of sodium triacetoxyborohydride, sodium cyanoborohydride, andsodium borohydride.
 100. The process of claim 85, wherein the reductiveamination reaction is carried out in the presence of a base.
 101. Theprocess of claim 100, wherein the base is selected from the groupconsisting of triethylamine, diisopropylethylamine,diisopropylisobutylamine, sodium acetate, potassium acetate, lithiumacetate, cesium acetate, rubidium acetate, trifluroacetate, andhydrobromide.
 102. The process of claim 100, wherein the base istriethylamine.
 103. The process of claim 102, wherein a hydrochloridesalt of the compound of formula

is used, wherein G and D are defined as in claim
 85. 104. The process ofclaim 85, wherein the reductive amination reaction is carried out in thepresence of a solvent selected from the group consisting of:dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide,N,N-dimethylacetamide, tetrahydrofuran, 2,-methyltetrahydrofuran,2,5-dimethyltetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane,methyltertbutylether, chloroform, and acetonitrile.